1-Substituted alkyl-2-oxo-hexahydroquinoxaline derivatives

ABSTRACT

1-Substituted alkyl-2-oxo-hexahydroquinoxaline derivatives of the formula ##STR1## wherein A is lower alkylene; R 1  is selected from the group consisting of alkyl, phenyl-lower alkyl, and substituted phenyl-lower alkyl; and R is selected from the group consisting of 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR2## in which R 5  is hydrogen, lower alkyl or aryl, R 6  is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, Ar is phenyl or phenyl substituted with C 1-3  alkyl, halogen, nitro, or lower alkoxy, A and R 1  are as defined above, R 2  and R 3  are each lower alkyl or together form tetramethylene, m is an integer from 4-6, and n is 2 or 3; and pharmaceutically acceptable salts thereof. The compounds are useful as agents for platelet aggregation inhibition, vasodilation and anti-lipoperoxide generation.

RELATION TO OTHER APPLICATION

The present invention is a division of our copending application Ser. No. 07/020,012, filed Feb. 25, 1987, now U.S. Pat. No. 4,837,319.

BACKGROUND OF THE INVENTION

This invention relates to novel 1-substituted alkyl-2-oxo-hexahydro quinoxaline derivatives, which are useful as pharmaceuticals for treating circulatory and metabolic disorders. The compounds of the invention are active as platelet aggregation inhibiting, vasodilating and/or antilipoperoxide generating agents.

Recently, a significant number of compounds having platelet aggregation inhibiting activity have been reported. Of these, the only known compounds having a pyrazine ring as the basic structure are tetramethyl pyrazine (16th Heterocyclic Chemistry Symposium (Osaka) pp. 65-68 (1984)) and 2-higher fatty acid acyloxymethyl pyrazine (Jap. Pat. Unexam. Publ. No. 59-219269).

It is of great importance to discover high quality pharmaceuticals having stronger inhibitory activities for platelet aggregation, in order effectively to treat circulatory and metabolic disorders.

We have found that 1-substituted alkyl-2-oxo-hexahydro quinoxaline derivatives display inhibitory action on platelet aggregation, vasodilation activity and/or anti-lipoperoxide generation, and are expected to have excellent pharmaceutical properties.

SUMMARY OF THE INVENTION

In the present invention, a compound of the formula ##STR3## is provided, wherein R is 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR4## in which R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, A and A₁ are lower alkylene, m is an integer of 4-6, n is an integer of 2--3, the above aryl is phenyl or phenyl substituted with C₁₋₃ alkyl, halogen, nitro or lower alkoxy, R₁ is alkyl or phenyl-lower alkyl optionally substituted, and R₂ and R₃ are ech lower alkyl or together form tetramethylene.

The compound [1] can be provided in salt form. The salts must be pharmacologically acceptable non-toxic salts thereof. Examples of such salts are salts of an inorganic acid such as hydrochloric, sulfuric, or phosphoric, and salts of an organic acid such as acetic, propionic, butyric, glycolic, gluconic, malic, tartaric, succinic, mandelic, aspartic, glutaric, methanesulfonic or toluenesulfonic. Salts of other known acids can be used as well.

DETAILED DESCRIPTION OF THE INVENTION

The compound [1] can be produced by the following processes:

Intermediate Compound [1a]

A process for the production of an intermediate compound [1a] wherein R is hydroxyl, and the compound produced thus has the formula ##STR5## wherein R₁, and A are defined as above.

The above compound [1a] can be produced by reacting a compound of the formula ##STR6## wherein R₁, is defined as above, with a hydroxyalkyl halide of the formula

    X-A-OH

where X is halogen and A is defined as above, in an organic solvent.

In the compound [2] above, R₁ is alkyl, optionally substituted phenyl, or optionally substituted phenyl-lower alkyl. "Alkyl", as used above, is defined as saturated or unsaturated C₁₋₂₀ alkyl, which may be branched or unbranched. Examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl or hexadecyl. "Optionally substituted phenyl", as used above, is defined as phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro, or lower alkoxy. "Optionally substituted phenyl-lower alkyl", as used above, is defined as phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy, in which lower alkyl means methyl, 2-ethyl, 1-ethyl, 3-propyl or 1-propyl. Examples are benzyl, p-chlorobenzyl, 2-phenylethyl and 1-phenylethyl.

The compound [2] , i.e. a 2-hydroxy-3-substituted hexahydro quinoxaline derivative, is produced by the process developed by the present invention, in which an α-amino acidamide, other than glycine, is reacted with 1,2-cyclohexanedione in an alkaline medium.

The group A in the above hydroxylalkyl halide is defined as above, namely, lower alkylene. Examples of lower alkylene are methylene, ethylene, methylmethylene, propylene, 1-methylethylene, 1,1-dimethylmethylene or 1-ethylmethylene; ethylene is preferred.

The group X in the above hydroxyalkyl halide is halogen, such as chloride or bromide, and in general chloride is preferred. The preferred hydroxyalkyl halide is ethylene chlorohydrin.

Reaction of the compound [2]with hydroxyalkyl halide proceeds in an organic solvent such as butanol.

The above reaction is preferably effected in an aqueous alkali solvent such as hydroxy alkali, and preferably, is possible, under heating. Isolation of the product [1a] can be performed by adding water to the reaction mixture and extracting with water-immiscible organic solvent.

Intermediate Compound [1b]

A process for the production of a second intermediate [1b] compound wherein R is halogen, and the compound produced thus has the formula ##STR7## wherein X is halogen, and A and R₁ are defined as above.

A compound [1b] can be produced by halogenating the compound [1a] above with halogenating agent.

The said halogenating agent may be any known halogenating agent. More specifically, known chlorination reagents or bromination reagents can be used. Conventional chlorination reagents such as SOCl₂, PCl₅ and POCl₃ can be applied. The halogenation reaction can be effected, in general, in an inert organic solvent such as chloroform. Reaction proceeds at room temperature. Isolation of the product [1b] can be performed by adding a water-immiscible organic solvent such as chloroform, washing with dilute aqueous alkali, dehydrating the organic layer and removing the solvent therefrom.

The compound [1b] can be used without purification, as by silica-gel column chromatography, as an intermediate in the synthesis of compounds [1c] and [1d] below.

Process A

A process for production of compound [1] wherein R is 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1c]):

A compound [1c] can be produced by reacting the above compound [1d] with an alkali metal salt of 1-methyl-5-mercaptotetrazole in an organic solvent.

Examples of the above alkali salts of 1-methyl-5-mercaptotetrazole are the corresponding sodium and potassium salts.

Reaction of the above compound [1b] and the said alkali metal salt of the mercapto compound proceeds, in general, in an organic solvent such as dimethyl formamide (DMF). Isolation of the product [1c] can be performed by removing the reaction solvent and extracting the residue with water-immiscible organic solvent in the presence of dilute aqueous alkali.

Process B

A process for production of compound [1] wherein R is a group other than 1-methyltetrazole-5-yl-thio (hereinafter designated as compound [1d]):

A compound [1d] can be produced by reacting a compound [1b] with an amine of the formula wherein R' is 1-imidazolyl, morpholino, ##STR8## wherein m is an integer of 4-6, is defined as pyrrolidine, piperidine or a hexamethyleneimine ring. R₅ means hydrogen, lower alkyl or aryl. The position of the R₅ group may be any position in the ring hereinabove except at position 1 (nitrogen). The above alkyl means branched or unbranched C₁₋₆ alkyl. Ar as used above means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy.

The group R₆ in the above ##STR9## is defined as hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl. Examples of the above alkyl are branched or unbranched C₁₋₄ alkyl such as methyl, 2-ethyl, 1-ethyl, propyl, isopropyl and 1-methylethyl. Examples of aryl are phenyl; or phenyl substituted with C₁₋₃ alkyl, halogen, nitro or lower alkoxy, such as tolyl, xylyl, p(m or o)-nitrophenyl, p(m or o)-fluorophenyl, 2,4(2,3-, 3,4-, 2,5-, 3,5- or 2,6-)-dichlorophenyl, p(m or o)-nitrophenyl, p(m or o)-methoxyphenyl, 2,3(2,4-, 3,4-, 2,5-, 3,5- or 2,6)-dimethoxyphenyl. The above lower alkanoyl is branched or unbranched C₂₋₄ alkanoyl such as acetyl, propionyl, butylryl, isobutyryl or sec-butyryl.

The ring of the group ##STR10## wherein N is integer of 2-3, is piperazine or homopiperazine. A is lower alkylene such as methylene, ethylene, methylmethylene, propylene, 1-methylethylene or 1-ethylmethylene, and preferred examples are methylene and ethylene. Ar as used above means phenyl or phenyl substituted with C₁₋₃ lower alkyl, halogen, nitro or lower alkoxy. Examples thereof have been set forth above.

Accordingly, specific examples of the amine (R'-H) are 1-imidazole, morpholine, pyrrolidine, piperidine, 4-methylpiperazine, 4-ethylpiperazine, 4-butylpiperazine, 4-(2-hydroxyethyl)-piperazine, 4-phenyl-piperazine, 4-(o-chlorophenyl)-piperazine, 4-(o-methoxyphenyl)-piperazine, 4(phenylacetyl)-piperazine, 4-benzoyl-piperazine, 4-(p-chlorobenzoyl)-piperazine, 4-(p-nitrobenzoyl)-piperazine, 4-(p-methoxybenzoyl)-piperazine, 4-(2,3-dimethoxybenzoyl)-piperazine, 4-(2,4-dimethoxybenzoyl)-piperazine, 4-(3,4-dimethoxybenzoyl)-piperazine, 4-(3,4,5-trimethoxybenzoyl)-piperazine, 4-benzenesulfonyl-piperazine, 4-(p-chlorobenzenesulfonyl)-piperazine, 4-(2-thienylacetyl)-piperazine, 4-benzyl-piperazine, 4-(p-methylbenzyl)-piperazine, 4-(p-chlorobenzyl)-piperazine, 4-(m-chlorobenzyl)-piperazine, 4-(o-chlorobenzyl)-piperazine, 4-(2,4-dichlorobenzyl)-piperazine, 4-(p-fluorobenzyl)-piperazine, 4-(p-nitrobenzyl)-piperazine, 4-(p-methoxybenzyl)-piperazine, 4-benzyl-homopiperazine, 4-(p-methylbenzyl)-homopiperazine, 4-(p-chlorobenzyl)-homopiperazine, 4-(p-fluorobenzyl)-homopiperazine, 4-(p-nitrobenzyl)-homopiperazine and 4-(p-methoxybenzyl)-homopiperazine. Reaction of the compound [1b] and the above amine ordinarily proceeds in an inert organic solvent such as benzene, under heating. In the reaction, hydrogen halogenide is generated so that the said reaction proceeds in the presence of acid binder, for example known tertiary organic amines such as triethylamine. The compound [1d] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with water-immiscible organic solvent such as benzene or chloroform.

Process C

A process for the production of compound [1] wherein R is ##STR11## in which R₆ is aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl, or thienyl-lower alkanoyl (hereinafter designated as compound [1e]).

A compound [1g] can be produced by Process B above, but is also produced by means of another method in which a compound of the formula ##STR12## wherein R₁ and A have the same meanings hereinbefore, is acylated with an organic acid or a reactive derivative thereof.

The above organic acid is aryl-lower fatty acid, arylcarboxylic acid, arylsulfonic acid or thienyl-lower fatty acid, in which aryl means phenyl or phenyl substituted with C₁₋₃ alkyl, halogen nitro or lower alkoxy, and lower fatty acid means a branched or unbranched C₁₋₄ fatty acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid or sec-butyric acid. Examples of organic acid are phenyl-acetic acid, benzoic acid, p-chlorobenzoic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, 2,3-dimethoxy benzoic acid, 2,4-dimethoxybenzoic acid, 3,4-dimethoxybenoic acid, 3,4,5-trimethoxybenzoic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-thienylacetic acid. Examples of reactive derivatives are known acylating agents for the amino group, for example acid halide, acid anhydride, mixed anhydride and activated ester. Also, the organic acid can itself be acylated in the presence of a condensation agent such as DCC. Because acid is co-generated in the reaction, the reaction may proceed in the presence of an acid binder, for example known tertiary organic amines such as pyridine or triethylamine. The acylating reaction proceeds in a conventional organic solvent. The produced compound [1l] can be isolated by pouring the reaction mixture into dilute aqueous alkali and extracting with a water-immiscible organic solvent.

The thus-obtained compound [1] is purified, if required, by column chromatography using silica-gel, activated alumina or adsorption resin with elution solvent such as chloroform-methanol or benzene-ethyl acetate.

A compound [1] is generally produced in the form of its free base, but it can also be produced in the form of a conventional salt thereof. For example, a hydrochloride can be prepared by dissolving a compound [1] in a lower alcohol such as methanol or ethanol, adding a slight molar excess of hydrochloric acid, and isolating the precipitated material, or if not precipitated, by adding ether therein to precipitate. The molar ratio of hydrochloric acid may be different according to the specific compound [1].

Examples of the compound [1] of the present invention as set forth in Table 1.

                                      TABLE 1                                      __________________________________________________________________________      ##STR13##  Me; Et; Pro; iso-Pro; Bu; iso-Bu; sec-Bu;                                          methyl ethyl propyl isopropyl butyl isobutyl sec-butyl                                ##STR14##                                               Compound No.                                                                           R.sub.1  R.sub.2                                                                           R.sub.3                                                                            A      R                                               __________________________________________________________________________     018     Me       Me Me  CH.sub.2 CH.sub.2                                                                      ##STR15##                                      019     Me       Me Me  "                                                                                      ##STR16##                                      020     Me       Me Me  "                                                                                      ##STR17##                                      021     Me       Me Me  "                                                                                      ##STR18##                                      022     Me       Me Me  "      1-imidazolyl                                    023     Me       Me Me  "                                                                                      ##STR19##                                      024     Me       Me Me  "                                                                                      ##STR20##                                      025     Me       Me Me  "                                                                                      ##STR21##                                      026     Me       Me Me  "      OH                                              027     Me       Me Me  "      SPh                                             028     Me       Me Me  "      S(1-methyltetrazole-5-yl)                       061     Me       Me Me  CH.sub.2 CH.sub.2                                                                     OCOMe                                           062     Me       Me Me  "      O CONHMe                                        063     Me       Me Me  "      OCONHPh                                         064     Me       Me Me  "      OCONHPhCl(p)                                    101     Me       Me Me  "                                                                                      ##STR22##                                      109     Ph       Me Me  "      OH                                              110     Ph       Me Me  "                                                                                      ##STR23##                                      111     Ph       Me Me  "                                                                                      ##STR24##                                      112     CH.sub.2 Ph                                                                             Me Me  "      OH                                              113     "        Me Me  "                                                                                      ##STR25##                                      114     "        Me Me  "                                                                                      ##STR26##                                      115     "        Me Me  "                                                                                      ##STR27##                                      116     "        Me Me  "                                                                                      ##STR28##                                      117     Pro      (CH.sub.2).sub.4                                                                      "                                                                                      ##STR29##                                      118     Pro      "      "                                                                                      ##STR30##                                      119     Pro      "      "                                                                                      ##STR31##                                      120     Pro      (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR32##                                      121     Pro      Me Me  "                                                                                      ##STR33##                                      122     Pro      Me Me  "                                                                                      ##STR34##                                      123     iso-Bu   Me Me  "                                                                                      ##STR35##                                      124     "        Me Me  "                                                                                      ##STR36##                                      125     "        Me Me  "                                                                                      ##STR37##                                      126     "        Me Me  "                                                                                      ##STR38##                                      127     "        (CH.sub.2).sub.4                                                                      "                                                                                      ##STR39##                                      128     "        "      "                                                                                      ##STR40##                                      129     "        "      "                                                                                      ##STR41##                                      130     Pro      Et Et  "                                                                                      ##STR42##                                      131     Pro      Et Et  "                                                                                      ##STR43##                                      132     Pro      Et Et  "                                                                                      ##STR44##                                      133     Pro      Et Et  "                                                                                      ##STR45##                                      134     Pro      Et Et  "                                                                                      ##STR46##                                      141     Bu       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR47##                                      142     Bu       "      "                                                                                      ##STR48##                                      143     Bu       "      "                                                                                      ##STR49##                                      144     Bu       "      "                                                                                      ##STR50##                                      145     Bu       "      "                                                                                      ##STR51##                                      146     Bu       "      "                                                                                      ##STR52##                                      147     CH.sub.2 Ph                                                                             Me Me  "      OCOMe                                           148     iso-Pro  Me Me  "                                                                                      ##STR53##                                      149     "        Me Me  "                                                                                      ##STR54##                                      150     "        Me Me  "                                                                                      ##STR55##                                      151     "        Me Me  "                                                                                      ##STR56##                                      152     sec-Bu   Me Me  "                                                                                      ##STR57##                                      153     "        Me Me  "                                                                                      ##STR58##                                      154     "        Me Me  "                                                                                      ##STR59##                                      155     "        Me Me  "                                                                                      ##STR60##                                      156     Bu       Me Me  "                                                                                      ##STR61##                                      157     Bu       Me Me  CH.sub.2 CH.sub.2                                                                      ##STR62##                                      158     Bu       Me Me  "                                                                                      ##STR63##                                      159     iso-Pro  Et Et  "                                                                                      ##STR64##                                      160     "        Et Et  "                                                                                      ##STR65##                                      161     "        Et Et  "                                                                                      ##STR66##                                      162     "        Et Et  "                                                                                      ##STR67##                                      163     "        Et Et  "                                                                                      ##STR68##                                      164     "        Et Et  "                                                                                      ##STR69##                                      165     "        Et Et  "                                                                                      ##STR70##                                      166     iso-Bu   Et Et  "                                                                                      ##STR71##                                      167     "        Et Et  "                                                                                      ##STR72##                                      168     "        Et Et  "                                                                                      ##STR73##                                      170     "        Et Et  "                                                                                      ##STR74##                                      171     sec-Bu   Et Et  "                                                                                      ##STR75##                                      172     "        Et Et  "                                                                                      ##STR76##                                      173     sec-Bu   Et Et  CH.sub.2 CH.sub.2                                                                      ##STR77##                                      174     "        Et Et  "                                                                                      ##STR78##                                      175     "        Et Et  "                                                                                      ##STR79##                                      176     "        Et Et  "                                                                                      ##STR80##                                      177     "        Et Et  "                                                                                      ##STR81##                                      178              Et Et  "                                                                                      ##STR82##                                      179     Bu       Et Et  "                                                                                      ##STR83##                                      180     Bu       Et Et  "                                                                                      ##STR84##                                      181     Bu       Et Et  "                                                                                      ##STR85##                                      182     Bu       Et Et  "                                                                                      ##STR86##                                      183     Bu       Et Et  "                                                                                      ##STR87##                                      185     Bu       Et Et  "                                                                                      ##STR88##                                      187     Et       Et Et  "                                                                                      ##STR89##                                      188     Et       Et Et  "                                                                                      ##STR90##                                      189     Et       Et Et  "                                                                                      ##STR91##                                      190     Et       Me Me  CH.sub.2 CH.sub.2                                                                      ##STR92##                                      191     Et       Me Me  "                                                                                      ##STR93##                                      192     Et       Me Me  "                                                                                      ##STR94##                                      193     Et       Me Me  "                                                                                      ##STR95##                                      250     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      "                                                                                      ##STR96##                                      251     "        "      "                                                                                      ##STR97##                                      252     "        "      "                                                                                      ##STR98##                                      253     "        "      "                                                                                      ##STR99##                                      254     "        "      "                                                                                      ##STR100##                                     255     (CH.sub.2).sub.5 CH.sub.3                                                               "      "                                                                                      ##STR101##                                     256     "        "      "                                                                                      ##STR102##                                     257     "        "      "                                                                                      ##STR103##                                     258     "        "      "                                                                                      ##STR104##                                     259     (CH.sub.2).sub.6 CH.sub.3                                                               "      "                                                                                      ##STR105##                                     260     "        "      "                                                                                      ##STR106##                                     261     (CH.sub.2).sub.6 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR107##                                     262     "        "      "                                                                                      ##STR108##                                     263     "        "      "                                                                                      ##STR109##                                     264     "        "      "                                                                                      ##STR110##                                     265     (CH.sub.2).sub.7 CH.sub.3                                                               "      "                                                                                      ##STR111##                                     266     "        "      "                                                                                      ##STR112##                                     267     "        "      "                                                                                      ##STR113##                                     268     "        "      "                                                                                      ##STR114##                                     269     "        "      "                                                                                      ##STR115##                                     270     "        "      "                                                                                      ##STR116##                                     271     (CH.sub.2).sub.8 CH.sub.3                                                               "      "                                                                                      ##STR117##                                     272     "        "      "                                                                                      ##STR118##                                     273     "        "      "                                                                                      ##STR119##                                     274     "        "      "                                                                                      ##STR120##                                     275     "        "      "                                                                                      ##STR121##                                     276     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR122##                                     277     "        "      "                                                                                      ##STR123##                                     278     "        "      "                                                                                      ##STR124##                                     279     "        "      "                                                                                      ##STR125##                                     280     (CH.sub.2).sub.13 CH.sub.3                                                              "      "                                                                                      ##STR126##                                     281     "        "      "                                                                                      ##STR127##                                     282     "        "      "                                                                                      ##STR128##                                     283     (CH.sub.2).sub.15 CH.sub.3                                                              "      "                                                                                      ##STR129##                                     284     "        "      "                                                                                      ##STR130##                                     285     "        "      "                                                                                      ##STR131##                                     286     "        "      "                                                                                      ##STR132##                                     287     Et       Me Me  "                                                                                      ##STR133##                                     288     Et       Me Me  "                                                                                      ##STR134##                                     289     Et       Me Me  "                                                                                      ##STR135##                                     290     Et       Me Me  "                                                                                      ##STR136##                                     291     CH.sub.2 Ph                                                                             Et Et  CH.sub.2 CH.sub.2                                                                      ##STR137##                                     292     "        Et Et  "                                                                                      ##STR138##                                     293     "        Et Et  "                                                                                      ##STR139##                                     294     "        Et Et  "                                                                                      ##STR140##                                     295     "        Et Et  "                                                                                      ##STR141##                                     296     "        Et Et  "                                                                                      ##STR142##                                     297     "        Et Et  "                                                                                      ##STR143##                                     305     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      "                                                                                      ##STR144##                                     306     "        "      "                                                                                      ##STR145##                                     307     "        "      "                                                                                      ##STR146##                                     308     "        "      "                                                                                      ##STR147##                                     309     "        "      "                                                                                      ##STR148##                                     310     "        "      "                                                                                      ##STR149##                                     311     "        "      "                                                                                      ##STR150##                                     312     "        "      "                                                                                      ##STR151##                                     313     (CH.sub.2).sub.5 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR152##                                     314     (CH.sub.2).sub.6 CH.sub.3                                                               "      "                                                                                      ##STR153##                                     315     "        "      "                                                                                      ##STR154##                                     316     "        "      "                                                                                      ##STR155##                                     317     "        "      "                                                                                      ##STR156##                                     318     "        "      "                                                                                      ##STR157##                                     319     "        "      "                                                                                      ##STR158##                                     320     "        "      "                                                                                      ##STR159##                                     321     (CH.sub.2).sub.7 CH.sub.3                                                               "      "                                                                                      ##STR160##                                     322     "        "      "                                                                                      ##STR161##                                     323     "        "      "                                                                                      ##STR162##                                     324     "        "      "                                                                                      ##STR163##                                     325     "        "      "                                                                                      ##STR164##                                     326     "        "      "                                                                                      ##STR165##                                     327     "        "      "                                                                                      ##STR166##                                     328     (CH.sub.2).sub.8 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR167##                                     329     "        "      "                                                                                      ##STR168##                                     330     "        "      "                                                                                      ##STR169##                                     331     "        "      "                                                                                      ##STR170##                                     332     "        "      "                                                                                      ##STR171##                                     334     (CH.sub.2).sub.9 CH.sub.3                                                               "      "                                                                                      ##STR172##                                     335     "        "      "                                                                                      ##STR173##                                     336     "        "      "                                                                                      ##STR174##                                     337     "        "      "                                                                                      ##STR175##                                     338     "        "      "                                                                                      ##STR176##                                     339     "        "      "                                                                                      ##STR177##                                     340     "        "      "                                                                                      ##STR178##                                     374     CH.sub.2 Ph                                                                             Et Et  "                                                                                      ##STR179##                                     375     "        Et Et  "                                                                                      ##STR180##                                     378     "        Et Et  "                                                                                      ##STR181##                                     380     CH.sub.2 Ph                                                                             Et Et  CH.sub.2 CH.sub.2                                                                      ##STR182##                                     384     CH.sub.2 PhCl(p)                                                                        Et Et  "                                                                                      ##STR183##                                     385     "        Et Et  "                                                                                      ##STR184##                                     386     "        Et Et  "                                                                                      ##STR185##                                     387     "        Et Et  "                                                                                      ##STR186##                                     454     Et       Me Me  "                                                                                      ##STR187##                                     455     Et       Me Me  "                                                                                      ##STR188##                                     456     Et       Me Me  "                                                                                      ##STR189##                                     457     Et       Me Me  "                                                                                      ##STR190##                                     458     Et       Me Me  "                                                                                      ##STR191##                                     459     Et       Me Me  "                                                                                      ##STR192##                                     460     Et       Me Me  "                                                                                      ##STR193##                                     461     Et       Me Me  "                                                                                      ##STR194##                                     462     Et       Me Me  "                                                                                      ##STR195##                                     463     Et       Me Me  "                                                                                      ##STR196##                                     464     Et       Me Me  CH.sub.2 CH.sub.2                                                                      ##STR197##                                     465     Et       Me Me  "                                                                                      ##STR198##                                     467     CH.sub.2 PhCl(p)                                                                        Et Et  "                                                                                      ##STR199##                                     470     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      "                                                                                      ##STR200##                                     471     "        "      "                                                                                      ##STR201##                                     472     "        "      "                                                                                      ##STR202##                                     473     "        "      "                                                                                      ##STR203##                                     474     "        "      "                                                                                      ##STR204##                                     475     "        "      "                                                                                      ##STR205##                                     476     CH.sub.2 CH.sub.2 Ph                                                                    "      "                                                                                      ##STR206##                                     477     "        "      "                                                                                      ##STR207##                                     478     "        "      "                                                                                      ##STR208##                                     479     "        "      "                                                                                      ##STR209##                                     480     "        "      "                                                                                      ##STR210##                                     481     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR211##                                     482     Et       (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                      ##STR212##                                     483     Et       "      "                                                                                      ##STR213##                                     484     Et       "      "                                                                                      ##STR214##                                     485     Et       "      "                                                                                      ##STR215##                                     486     Et       "      "                                                                                      ##STR216##                                     487     (CH.sub.2).sub.13 CH.sub.3                                                              "      "                                                                                      ##STR217##                                     488     "        "      "                                                                                      ##STR218##                                     489     "        "      "                                                                                      ##STR219##                                     490     "        "      "                                                                                      ##STR220##                                     611     Me       Me Me  "                                                                                      ##STR221##                                     612     Ph       Me Me  "      Cl                                              613     CH.sub.2 Ph                                                                             Me Me  "      Cl                                              614     Pro      (CH.sub.2).sub.4                                                                      "      OH                                              615     Pro      "      "      SPh                                             616     Pro      Me Me   "     OH                                              617     iso-Bu   Me Me   "     OH                                              618     iso-Bu   (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              619     "        Me Me  "                                                                                      ##STR222##                                     620     Pro      Et Et  "      OH                                              621     Bu       (CH.sub.2).sub.4                                                                      "      OH                                              622     iso-Pro  Me Me  "      OH                                              623     sec-Bu   Me Me  "      OH                                              624     Bu       Me Me  "      OH                                              625     iso-Pro  Et Et  "      OH                                              626     iso-Bu   Et Et  "      OH                                              627     sec-Bu   Et Et  "      OH                                              628     Bu       Et Et  "      OH                                              629     Et       Et Et  "      OH                                              630     Et       Me Me  "      OH                                              631     (CH.sub.2).sub.4 CH.sub.3                                                               (CH.sub.2).sub.4                                                                      "      OH                                              632     (CH.sub.2).sub.5 CH.sub.3                                                               "      "      OH                                              633     (CH.sub.2).sub. 6 CH.sub.3                                                              "      "      OH                                              634     (CH.sub.2).sub.7 CH.sub.3                                                               "      "      OH                                              635     (CH.sub.2).sub.8 CH.sub.3                                                               "      "      OH                                              636     (CH.sub.2).sub.9 CH.sub.3                                                               "      "      OH                                              637     (CH.sub.2).sub.11 CH.sub.3                                                              (CH.sub.2).sub.4                                                                      CH.sub.2 CH.sub.2                                                                     OH                                              638     (CH.sub.2).sub.13 CH.sub.3                                                              "      "      OH                                              639     (CH.sub.2).sub.15 CH.sub.3                                                              "      "      OH                                              640     CH.sub.2 Ph                                                                             Et Et  "      OH                                              641     CH.sub.2 PhCl(p)                                                                        Et Et  "      OH                                              642     Me       Me Me  "                                                                                      ##STR223##                                     643     CH.sub.2 Ph                                                                             (CH.sub.2).sub.4                                                                      "      OH                                              644     CH.sub.2 Ph                                                                             "      "      Cl                                              645     CH.sub.2 CH.sub.2 Ph                                                                    "      "      OH                                              646     Et       "      "      OH                                              647     CH.sub.2 PhCl(p)                                                                         Et                                                                               Et  "      Cl                                              __________________________________________________________________________

The pharmacological activity of the present compounds [1] is illustrated below. All the compounds [1] used in the pharmacological tests were tested in the form of the hydrochloride salt thereof.

1. Platelet aggregation inhibition

Sample solution containing a compound [1] (final concentration 500 or 100 μM) is added to rabbit platelet plasma to which was added 10% by volume of a 3.8% sodium citrate solution, and the mixture is incubated at 37° C. for 3 mins. A platelet activation factor (PAF, final concentration 10-50 ng/ml) or collagen (final concentration 2.5 μg/ml) is added thereto as an aggregating agent, the platelet aggregation activity is measured with an aggrigometer. The results of assays for PAF-induced aggregation are shown in Table 2, and those for collagen-induced aggregation are shown in Table 3, which tables show the strong platelet aggregation inhibitory activity of the compounds [1] of the present invention.

                  TABLE 2                                                          ______________________________________                                         Platelet Aggregation Inhibitory Action on                                      PAF-Induced Aggregation                                                                Concen-  Inhibi-         Concen-                                                                               Inhibi-                                Compound                                                                               tration  tion    Compound                                                                               tration                                                                               tion                                   No.     μM    %       No.     μM  %                                      ______________________________________                                         114     500      63      174     500    96                                     115     "        88      175     "      94                                     116     "        76      176     "      81                                     120     "        83      177     "      79                                     126     "        54      178     "      94                                     128     "        83      179     "      93                                     129     "        79      180     "      90                                     132     "        72      183     "      85                                     133     "        63      185     "      61                                     134     "        57      188     "      86                                     142     "        82      189     "      69                                     143     "        87      191     "      62                                     145     "        52      253     100    93                                     146     "        87      263     "      70                                     154     "        54      306     "      60                                     158     "        64      308     "      40                                     160     "        97      310     "      46                                     161     "        93      313     "      48                                     162     "        93      316     "      49                                     163     "        62      321     "      43                                     165     "        92      323     "      43                                     166     "        87      326     "      51                                     168     "        76      332     "      46                                     170     "        80      386     "      71                                     172     "        57      387     "      41                                     173     "        61                                                            ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                         Platelet Aggregation Inhibitory Action on                                      Collagen-Induced Aggregation                                                           Concen-  Inhibit-        Concen-                                                                               Inhibi-                                Compound                                                                               tration  ion     Compound                                                                               tration                                                                               tion                                   No.     μM    %       No.     μM  %                                      ______________________________________                                         114     100      50      289     100    58                                     115     "        50      292     "      50                                     251     "        78      384     "      76                                     252     "        42      386     "      71                                     253     "        52      467     "      80                                     255     "        48      471     "      81                                     263     "        73      473     "      64                                     265     "        45      474     "      81                                     287     "        50      475     "      81                                     288     "        72      477     "      72                                     ______________________________________                                    

2. Vasodilation activity

A dog, pretreated with morphine (81.5 mg/kg, sc) is anesthetized with urethane (8450 mg/kg, iv) and α-chloralose (45 mg/kg, iv), and immobilized in the dosal position. Right femoral arterial blood is introduced into a left femoral artery via a perfusion pump, and Sterling's resistance is connected to the exosomatic circulatory system to perfuse blood to a left back limb at constant pressure. The perfusion pressure is set with a valve at slightly higher than that of the average blood pressure of the animal. Sample (100 μg) dissolved in physiological saline solution is administered to a right femoral artery, and changes in blood flow are measured. Vasodilation activity is measured as a relative activity, by defining as 100% the increased rate of blood flow when 30 μg papaverine is administered intra-arterially. The results are shown in Table 4, where it will be seen that the compounds [1] of the present invention have strong vasodilation activity.

                  TABLE 4                                                          ______________________________________                                         Vasodilation Activity                                                                    Vasodilation           Vasodilation                                  Compound No.                                                                             activity % Compound No.                                                                               activity %                                    ______________________________________                                         023       118        158         139                                           024       182        160         117                                           025       112        161         214                                           114       174        162         212                                           115       210        165         222                                           116       147        166         153                                           119       132        168         205                                           120       223        170         178                                           122       161        171         122                                           124       278        174         179                                           125       220        175         151                                           126       310        176         159                                           128       155        177         122                                           129       201        178         111                                           131       158        179         139                                           132       231        180         136                                           133       251        181         125                                           134       143        183         107                                           142       151        185         115                                           143       119        188         188                                           144       120        189         133                                           146       125        191         165                                           149       122        193         226                                           150       229        254         232                                           151       121        287         170                                           153       197        288         232                                           157       162        297         229                                           ______________________________________                                    

3. Antioxidant activity

Antioxidant activity is determined according to the method of Stocks et al. (Clin. Sci. Mol. Med., 47: 215 (1974)). Rat cerebrum is added to ice-cooled 40 mM phosphate saline solution (PBS) (pH 7.4, 4 ml buffer per 1 g cerebrum), homogenized and centrifuged (1000×g, 4° C., 10 min.) to obtain supernatant solution. The supernatant solution is diluted five-fold with the above ice-cooled PBS solution, and to a 0.9 ml aliquot thereof is added a sample containing a compound [1] (0.1 ml, final concentration 100 μM) dissolved in ethanol. The resultant mixture is incubated at 37° C. for 15 mins., 35% perchloric acid (0.2 ml) is added, and the mixture is then ice-cooled to stop the reaction and centrifuged (1300×g, 4° C., 10 min.). 0.5 ml thiobarbituric acid (5 g/lit. of 50% acetic acid) is added to the supernatant solution (1 ml), whereafter it is heated at 100° C. for 30 mins. and ice-cooled, so as to measure its absorbency at 532 nm. The amount of lipoperoxide thus-generated is expressed as an amount of malondialdehyde. The results are shown in Table 5, where it will be seen that the compounds [1] of the present invention inhibit lipoperoxide generation.

                  TABLE 5                                                          ______________________________________                                         Antioxidant Activity                                                           Compound  Inhibition   Compound  Inhibition                                    No.       %            No.       %                                             ______________________________________                                         115       44           307       50                                            119       41           308       57                                            129       53           309       71                                            132       53           310       79                                            133       51           311       89                                            134       49           312       93                                            142       48           313       89                                            143       53           314       75                                            150       45           315       82                                            154       51           316       86                                            158       44           317       68                                            160       41           318       82                                            161       76           319       89                                            162       47           320       86                                            165       70           321       75                                            168       59           322       79                                            175       49           323       75                                            176       88           324       64                                            177       73           325       92                                            178       67           326       88                                            180       69           327       92                                            183       41           328       72                                            185       63           329       88                                            256       66           330       92                                            258       87           331       88                                            260       62           332       80                                            264       79           334       56                                            267       68           335       80                                            268       77           336       96                                            269       70           337       88                                            270       93           338       80                                            272       83           339       72                                            273       77           340       92                                            274       77           378       52                                            275       80           385       67                                            276       67           386       50                                            277       70           387       77                                            278       87           467       61                                            279       73           472       53                                            280       67           473       58                                            281       77           478       59                                            282       87           479       53                                            283       53           487       72                                            295       55           488       84                                            305       61           489       78                                            306       54           490       75                                            ______________________________________                                    

As explained hereinabove, a compound [1] of the present invention or its corresponding salt inhibits platelet aggregation, has vasodilating activity, and/or inhibits lipoperoxide generation, and is useful in pharmaceutical form for treating circulatory and metabolic disorders.

EXAMPLES

The following examples are illustrative of the present invention, but are not to be construed as limiting.

In the examples, the Rf value of silica-gel thin layer chromatography (TLC) is either specified by or measured using the following carrier and developing solvent:

Carrier: silica-gel, Kieselgel 60 F₂₅₄ (Merck)

Developer: chloroform-methanol (20:1)

Physical properties of the compounds [1] obtained in the following examples are shown in Table 27.

Example 1

1-(2-hydroxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 026):

2-Hydroxy-3,5,6-trimethylpyrazine (13.8 g, 0.1M) and 5N NaOH (100 ml, 0.5M) were added to t-butanol (200 ml). Ethylene chlorohydrin (40.3 g, 0.5M) was added thereto and the mixture was stirred at 60° C. for 2 hours. Water was added to the reaction mixture, which was then extracted 10 times with chloroform (100 ml), and the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Wako Pure Chem. Co., C-200) and eluted with chloroform-methanol (300:1) to obtain the product (14.4 g, yield: 79.1%). Dihydrochloride: m.p.: 140°-144° C.

Examples 2-9

1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine:

Thionylchloride (0.86 ml, 12 mM) in chloroform (0.5 ml) was added dropwise under ice-cooling to the compound 026 (1.82 g, 10 mM) suspended in chloroform (5 ml) and stirred at room temperature for 3 hours to chlorinate. The reaction mixture was poured into dilute aqueous Na₂ CO₃, extracted three times with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo.

The obtained chlorinated compound was dissolved in benzene (60 ml), base (20 mM) and triethylamine (2.8 ml, 20 mM) were added thereto, and the mixture was refluxed. The reaction mixture was washed with dilute aqueous Na₂ CO₃ and the aqueous layer was extracted two times with benzene. The combined benzene layer, which was dried with anhydrous sodium sulfate, was concentrated in vacuo. The residue was chromatographed on a silica-gel (80 g) column using an elution solvent of chloroform-methanol to obtain the compounds in Table 6.

Table 6 shows the identify of the base, the reflux time and the ratio of chloroform-methanol mixture used in each of the above examples.

Examples 10-11

1-(2-substituted thioethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine:

Compound 026 (0.91 g, 5 mM) was chlorinated with thionylchloride according to the same method used in Examples 2-9. The thus-obtained chlorinated compound was dissolved in dimethylformamide (DMF, 10 ml), sodium mercaptan (5 mM) was added, and the mixture was stirred at room temperature for 2 days. DMF was driven off in vacuo. Dilute aqueous K₂ CO₃ solution was added to the residue, whereafter it was extracted with chloroform, dried by adding anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica-gel (C-200, 50 g) column eluted with benzene-ethyl acetate (5:1) to obtain the product in Table 7.

Table 7 shows the particular mercaptans used in the above examples.

Example 12

1,4-bis[2-(3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine-1-yl)ethyl]piperazine (compound 101):

Chloroform (3 ml) in solution with thionylchloride (4.3 ml, 60 mM) was added dropwise under ice-cooling to compound 026 (9.10 g, 50 mM) suspended in chloroform (15 ml). After stirring at room temperature for 3 hours, the reaction mixture was poured into dilute aqueous K₂ CO₃ and extracted with chloroform (200 ml). The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in benzene (300 ml), piperazine (2.15 g) and triethylamine (0.8 ml, 50 mM) were added, and the mixture was refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K₂ CO₃ and the aqueous layer was extracted with chloroform. The chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 180 g), and eluted with chloroform-methanol (100:1) to obtain compound 101 (7.60 g, yield: 73.2%).

Example 13

1-(2-piperazinoethyl)-3,5,6-trimethyl-1,2-dihydropyrazine (compound 642):

Piperazine (17.2 g, 0.2M) and triethylamine (28 ml, 0.2M) were used in the method of Example 12, the other conditions being preserved, to obtain compound 642 (5.52 g, yield: 44.2%) which displayed a lower Rf value relative to compound 101.

Example 14

1-(2-hydroxyethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 109):

Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-phenyl-5,6-dimethyl-pyrazine (10.0 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 2.5 hours. Water was added to the reaction mixture, the mixture extracted with chloroform, and the extract dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 130 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 109 (8.73 g, yield: 71.5%).

Example 15

1-(2-chloroethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 612):

Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to compound 109 (1.22 g, 50 mM) dissolved in chloroform (10 ml), and stirred at room temperature for 3 hours. Chloroform was added to the reaction mixture, whereafter the mixture was washed with dilute aqueous K₂ CO₃ and the resultant aqueous layer extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), and eluted with chloroform to obtain compound 612 (0.59 g, yield: 42.7%).

Examples 16-17

1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

Base (5 mM) and triethylamine (0.70 ml, 5 mM) were added to compound 612 (0.66 g, 2.5 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) and eluted with chloroform-methanol to obtain the compounds in Table 8.

Table 8 identifies the base, reflux time and the ratio of the chloroform-methanol mixture used in the above examples.

Example 18

1-(2-hydroxyethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 112):

Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-benzyl-5,6-dimethyl-pyrazine (2.14 g, 10 mM) and 5N NaOH (10 ml) in t-butanol (30 ml), and stirred at 60° C. for 2.5 hours. Water (100 ml) was added to the reaction mixture, and the mixture was extracted three times with chloroform, the extract dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g) and eluted with chloroform-methanol (100:1) to obtain compound 112 (2.22 g, yield: 86.0%).

Example 19

1-(2-chloroethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 613):

Thionylchloride (0.42 ml, 6.0 mM) was added dropwise under ice-cooling to a compound 112 (1.29 g, 5 mM) dissolved in chloroform (6 ml), and stirred at room temperature for 5 hours. Chloroform (70 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, the resulting aqueous layer being twice extracted with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 25 g), packed with chloroform, and eluted with chloroform to obtain compound 613 (1.00 g, yield: 87.5%).

Examples 20-23

1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo 1,2-dihydropyrazine:

Base (6.0 mM) and triethylamine (0.84 ml, 6.0 mM) were added to compound 613 (0.83 g, 3.0 mM) dissolved in benzene (15 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the aqueous layer extracted with further benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 9.

Table 9 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 24-28

1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted three times with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 120 g) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 10.

Table 10 identifies the specific 2-hydroxy-3-alkyl-5,6-dimethyl-pyrazine, its amount used, reaction time in hours, and ratio of mixture of chloroform-methanol used in each of the above examples.

Examples 29-46

1-(2-substituted ethyl)-3-alkyl-5,6-trimethyl-2-oxo 1,2-dihydropyrazine:

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 24-28, and the reaction mixture was dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml) and base (8 mM) were added to the residue and the resultant mixture was refluxed. Chloroform (100-120 ml) was added to the reaction mixture and washed with dilute aqueous K₂ CO₃. The aqueous layer was extracted twice with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 11.

Table 11 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 47-49

1-(2-hydroxyethyl)-3-alkyl-5,6-dimethyl-2-oxo- 1,2,5,6,7,8-hexahydroquinoxaline:

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) and eluted with chloroform-methanol to obtain the compounds (hydroxy ethyl form) of Table 12.

Table 12 identifies the specific 2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline (group R₁), its amount used, reaction time in hours, and ratio of the chloroform-methanol mixture used in the above examples.

Examples 50-62

1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline:

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 47-49, dissolved in chloroform and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the reaction mixture, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted with chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 13.

Table 13 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 63-68

1-(2-hydroxyethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine:

Aqueous 5N NaOH (10 ml, 50 mM), t-butanol (30 ml) and ethylene chlorohydrin (50 mM) were added to 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (10 mM) and stirred at 60° C. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo.

The residue was charged on a silica-gel column (C-200) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds in Table 14.

Table 14 identifies the specific 2-hydroxy-3-alkyl-5,6-diethyl-pyrazine (group R₁), its amount used, reaction time in hours, amount of silica-gel and ratio of chloroform-methanol mixture used in each of the above examples.

Examples 69-101

1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine:

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to the hydroxy ethyl form (4 mM) of the compounds obtained in Examples 63-68, dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with further chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue, followed by refluxing. Chloroform (100 ml) was added to the reaction mixture, and the mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted with additional chloroform. The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 15.

Table 15 identifies the starting material (hydroxy ethyl form), base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Example 102

1-(2-hydroxyethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 630):

Ethylene chlorohydrin (32.21 g, 0.4M) was added to a solution of 2-hydroxy-3-ethyl-5,6-dimethyl-pyrazine (12.16 g, 80 mM) and 5N NaOH (80 ml) in t-butanol (240 ml), and stirred at 60° C. for 3 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, the mixture extracted with chloroform, and the resultant aqueous layer extracted twice with further chloroform. The combined chloroform layers were dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 250 g) packed with chloroform and eluted with chloroform-methanol (from 200:1 to 50:1) to obtain compound 630 (12.31 g, yield: 78.5%).

Examples 103-110

1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

Thionylchloride (0.43 ml) was added dropwise under ice-cooling to compound (0.98 g, 5 mM) dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform (50 ml) was added to the reaction mixture, the mixture then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with additional chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. Benzene (30 ml), triethylamine (1.40 ml) and base (10 mM) were added to the residue and refluxed. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted twice with chloroform (50 ml). The chloroform layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 70 g) packed with chloroform, and eluted with chloroform-methanol to obtain the compounds shown in Table 16.

Table 16 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Example 111

1-(2-hydroxyethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 640):

Ethylene chlorohydrin (20.15 g, 0.25M) was added to a solution of 2-hydroxy-3-benzyl-5,6-diethyl-pyrazine (12.10 g, 50 mM) and 5N NaOH (50 ml) in t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added thereto and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 230 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 640 (12.31 g, yield: 58.7%).

Examples 112-122

1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

Thionylchloride (0.34 ml) was added dropwise under ice-cooling to compound 640 (1.15 g, 4.0 mM) dissolved in chloroform (5 ml) and stirred at room temperature for one hour. Chloroform (100 ml) was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer extracted twice with additional chloroform (30 ml). The chloroform layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. Triethylamine (1.12 ml, 8 mM) and base (8 mM) were added to the residue dissolved in benzene (30 ml), followed by refluxing. The reaction mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted twice with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol to obtain the compounds shown in Table 17.

Table 17 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Example 123

1-(2-hydroxyethyl)-3-p-chlorobenzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine (compound 641):

Ethylene chlorohydrin (16.11 g, 0.20M) was added to a solution of 2-hydroxy-3-p-chlorobenzyl-5,6-dimethylpyrazine (11.06 g, 40 mM) in aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Dilute aqueous K₂ CO₃ was added to the residue, the resulting mixture being extracted three times with chloroform, dried wit anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 300 g) packed with chloroform and eluted with chloroform-methanol (100:1) to obtain compound 641 (9.73 g, yield: 75.9%).

Example 124

1-(2-chloroethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine (compound 647):

Thionylchloride (1.20 ml) was added dropwise to compound 641 (4.16 g, 13 mM) dissolved in chloroform (20 ml) under ice-cooling and stirred at room temperature for 1.5 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, the resulting mixture being extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647 (4.27 g, yield: 96.9%).

Examples 125-129

1-(2-substituted ethyl) 3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine:

Base (6 mM) and triethylamine were added to chloroethyl compound 649 (1.023 g, 3 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was poured into dilute aqueous K₂ CO₃, the resultant aqueous layer being washed and extracted with benzene. The benzene layer was combined, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charge don a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds of Table 18.

Table 18 identifies the base, reflux time and ratio of chloroform-methanol mixture used in the above examples.

Examples 130-138

1-(2-hydroxyethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline:

Ethylene chlorohydrin (4.03 g, 50 mM) was added to a solution of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (10 mM) in aqueous 5N NaOH (10 ml, 50 mM) and t-butanol (30 ml), and stirred at 60° C. for 4 hours. Water was added to the reaction mixture, which mixture was then extracted with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200) packed with chloroform and eluted to obtain the compounds (hydroxy ethyl form) of Table 19.

The kind of 2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline (group R₁), its amount used, amount of silica gel used in column chromatography and kind of elution solvent are illustrated in Table 19.

Examples 139-214

1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,3,5,6,7,8-hexahydroquinoxaline:

Thionylchloride (1.3 equivalent) was added dropwise under ice-cooling to the hydroxy ethyl form (3-5 mM) of the compounds obtained in Examples 130-138, dissolved in chloroform (3-5 ml) and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted three times with chloroform (50 ml), dried with anhydrous sodium sulfate, and concentrated in vacuo. Benzene (30 ml), triethylamine (2 eq.) and base (2 eq.) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K₂ CO₃, then extracted several times with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 60 g) and eluted with chloroform-methanol (200:1) to obtain the compounds shown in Table 20.

The kind of starting material (hydroxy ethyl form), amount thereof used, base and relfux time are shown in Table 20.

Example 215

1-(2-piperazinyl ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

Thionylchloride (6.6 ml) was added dropwise under ice-cooling to compound 630 (13.72 g, 70 mM) dissolved in chloroform (70 ml), and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which was then extracted with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. Triethylamine (19.6 ml, 0.14M) and anhydrous piperazine (64.4 g, 0.75M) were added to the residue dissolved in benzene (420 ml), and refluxed for 3 hours. The reaction mixture was washed with dilute aqueous K₂ CO₃. The resultant aqueous layer was extracted with benzene. The benzene layer was combined, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 375 g) packed with chloroform and eluted with chloroform-methanol (10:1) to obtain compound 454 (13.66 g, yield: 73.9%).

Examples 216-226

1-[2-(4'-arylpiperazinyl) ethyl]-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine:

(a) Acid chloride method:

Triethylamine (0.84 ml, 6 mM) was added to compound 454 (0.81 g, 3 mM) dissolved in chloroform (10 ml), and acid chloride (3 mM) was added thereto under ice-cooling. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted three times with chloroform. The combined chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 80 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 21.

(b) Mixed anhydride method:

Triethylamine (0.70 ml) was added to the carboxylic acid (5 mM) dissolved in tetrahydrofuran (10 ml). After pivaloyl chloride (0.61 g, 5 mM) was added dropwise thereto at -5° C. and stirred for 30 mins., a solution of compound 454 (1.06 g, 4 mM) in chloroform was added dropwise. Reaction was continued under gradually increasing temperature, up to room temperature. The reaction mixture was thereafter treated as in method (a) above, to obtain the products shown in Table 21.

Acylation method, acylating agent used, reaction time and ratio of chloroform-methanol mixture are shown in Table 21.

Example 227

1-(2-hydroxyethyl-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 643):

Ethylene chlorohydrin (16.10 g, 0.2M) was added to a solution of 2-hydroxy-3-benzyl-5,6,7,8-tetrahydro quinoxaline (9.60 g, 40 mM) in dilute aqueous 5N NaOH (40 ml) and t-butanol (120 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. The residue was extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 220 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 643 (10.90 g, yield: 83.8%).

Example 228

1-(2-chloroethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 644):

Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml), and stirred at room temperature for 2 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain compound 644 (7.55 g, yield: 78.0%).

Examples 229-234

1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline:

Base (7 mM) and triethylamine (0.98 ml) were added to compound 644 (1.05 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 22.

The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 22.

Example 235

1-(2-hydroxyethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 645):

Ethylene chlorohydrin (9.0 g) was added to a solution of 2-hydroxy-3-(2-phenylethyl)-5,6,7,8-tetrahydro quinoxaline (5.59 g, 22 mM) in aqueous 5N NaOH and t-butanol (60 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo, water was added to the residue, and the mixture was extracted three times with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (200:1) to obtain compound 645 (6.73 g, yield: 90.9%).

Example 236

1-(2-chloroethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 647):

Thionylchloride (2.05 ml) was added dropwise under ice-cooling to compound 645 (6.49 g, 22.1 mM) dissolved in chloroform (25 ml), and stirred at room temperature for 2 hours. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted twice with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo to obtain compound 647, which was used without further purification in the following reactions.

Examples 237-241

1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline:

Base (7 mM) and triethylamine (0.98 ml) were added to compound 647 (1.11 g, 3.5 mM) dissolved in benzene (30 ml), and refluxed. The reaction mixture was washed with dilute aqueous K₂ CO₃, and the resultant aqueous layer was extracted with benzene. The combined benzene layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200), 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 23.

The kind base, reflux time and ratio of chloroform-methanol mixture are shown in Table 23.

Example 242

1-(2-hydroxyethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 646):

Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) in dilute aqueous 5N NaOH (50 ml) and t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Water was added to the residue, which residue was then extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100:1) to obtain compound 646 (9.30 g, yield: 83.8%).

Examples 243-248

1-(2-substituted ethyl)-3-ethyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline:

Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 646 (1.11 g, 5 mM) dissolved in chloroform (4 ml), and stirred at room temperature for one hour. Dilute aqueous K₂ CO₃ was added to the reaction mixture, which mixture was then extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo.

Benzene (30 ml), triethylamine (1.4 ml) and base (10 mM) were added to the residue, followed by refluxing. The reaction mixture was poured into dilute aqueous K₂ CO₃ and extracted with benzene. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 65 g) packed with chloroform and eluted with chloroform-methanol to obtain the compounds shown in Table 24.

The kind of base, reflux time and ratio of chloroform-methanol mixture are shown in Table 24.

Example 249

1-(2-acetoxyethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine (compound 061):

Acetic anhydride (2 ml) was added under ice-cooling to compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and dilute aqueous K₂ CO₃ was added thereto, the resultant mixture being extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5:1) to obtain compound 061 (0.58 g, yield: 51.8%).

Example 250

1-(2-phenylthioethyl)-3-propyl-2-oxo-1,2,5,6,7,8-hexahydroquinoxaline (compound 615):

Thionylchloride (0.47 ml) was added dropwise under ice-cooling to compound 614 (1.18 g, 5 mM, hydroxy ethyl form) as obtained in Example 47 dissolved in chloroform (5 ml), and stirred at room temperature for one hour. Chloroform was added to the reaction mixture, which mixture was then washed with dilute aqueous K₂ CO₃ and extracted with chloroform. The combined chloroform layer was dried with anhydrous magnesium sulfate and concentrated in vacuo.

Sodium thiophenolate (0.66 g) was added to the residue dissolved in DMF (20 ml), and stirred at room temperature for 2 days. DMF was distilled off in vacuo, dilute aqueous K₂ CO₃ was added to the residue, and the resulting mixture was extracted with chloroform. The extract was dried with anhydrous sodium sulfate and concentrated in vacuo.

The residue was charged on a column of silica-gel (C-200, 50 g) and eluted with benzene-ethyl acetate (5:1) to obtain compound 615 (1.32 g, yield: 80.7%).

Comparative Example 1

2-hydroxy-3-ethyl-5,6,7,8-tetrahydroquinoxaline:

1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of α-aminobutylamide (5.1 g, 50 mM) at -30° C., and aqueous 12.5N NaOH (5 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., whereafter the cooling was removed and the mixture was stirred at room temperature for 3 hours. Concentrated hydrochloric acid (6.25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (5 g) was added after 10 mins., the methanol being distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (5.3 g, yield: 60%, m.p.: 152°-153° C.).

NMR (CDCl₃) δ (ppm): 1.25 (t, 3H, --CH₂ CH₃), 1.7-1.9 (m, 4H, 6-H₂, 7-H₂), 2.5-2.8 (m, 4H, 5-H₂, 8-H₂), 2.80 (q, 2H, --CH₂ CH₃), 13.06 (br. s, 1H, OH)

Mass (CI): 179 (M⁺ +1)

Comparative Example 2

2-hydroxy-3-propyl-5,6,7,8-tetrahydroquinoxaline:

1,2-cyclohexanedione (5.4 g, 48 mM) was added all at once to a methanol solution (80 ml) of norvalineamide hydrochloride (6.1 g, 40 mM) at -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at -30° C. for 30 mins., cooling was removed, and the mixture stirred at room temperature for 3 hours. Conc. hydrochloric acid (10 ml) was added to the reaction mixture under ice-cooling, sodium bicarbonate (8 g) was added after 10 mins., the methanol then being distilled off in vacuo. The residue was extracted with chloroform, and the extract washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product as colorless crystals (3.8 g., yield: 50%, m.p.: 131°-133° C.).

NMR (CDCl₃) δ (ppm: 1.00 (t, 3H, --CH₂ CH₂ CH₃), 1.55-1.90 (m, 4H, 6-H, --CH₂ CH₂ CH₃, 6-H₂, 7-H₂), 2.67-2.83 (m, 6H, --CH₂ CH₂ CH₃, 5-H₂, 6-H₂), 13.09 (br. s, 1H, OH)

Mass (CI): 193 (M⁺ +1)

Comparative Examples 3-13

2-hydroxy-3-alkyl-5,6,7,8-tetrahydroquinoxaline:

1,2-cyclohexanedione (6.72 g, 60 mM) was added all at once to a methanol solution (100 ml) of α-amino acidamide hydrochloride (50 mM) at -30° C., and aqueous 12N NaOH (10 ml) was added dropwise thereto. The reaction mixture was stirred for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 5 hours. Conc. hydrochloric acid (12.5 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (10 g) was added after 10 mins., whereafter the methanol was distilled off in vacuo. The residue was extracted with chloroform, and the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product shown in Table 25.

The kind of product, yield (weight and %) and physical properties are shown in Table 25.

Comparative Example 14

2-hydroxy-3-benzyl-5,6,7,8-tetrahydroquinoxaline:

A methanol (30 ml) solution of 1,2-cyclohexanedione (13.44 g, 0.12M) was added to phenylalanineamide hydrochloride (20.05 g, 0.1M) dissolved in methanol (200 ml) under cooling below -30° C., and aqueous 12.5N NaOH (20 ml) was added dropwise thereto. The reaction mixture was stirred under -30° C. for 30 mins., whereafter cooling was removed and the mixture was stirred at room temperature for 3 hours. Conc. hydrochloric acid (25 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (15 g) was added after 10 mins. stirring the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, and the extract was washed with water, dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (19.7 g, yield: 82.1%).

NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.4-2.7 (m, 4H), 4.02 (s, 2H), 7.0-7.4 (m, 5H)

Mass (CI): 241 (M⁺ +1)

Comparative Example 15

2-hydroxy-3-(phenylethyl)-5,6,7,8-tetrahydroquinoxaline:

A methanol (20 ml) solution of 1,2-cyclohexanedione (5.38 g) was added to a methanol suspension (100 ml) of α-amino-(3-phenyl)-butylamide hydrochloride (8.58 g, 40 mM) at below -30° C., and aqueous 12.5N NaOH (8 ml) was added dropwise thereto. The reaction mixture was stirred at below -30° C. for 30 mins., cooling was removed, and the mixture was stirred at room temperature for 6 hours. Conc. hydrochloric acid (8 ml) was added to the reaction mixture under ice-cooling, and sodium bicarbonate (6.0 g) was added after 10 mins. stirring, the methanol then being distilled off in vacuo. The residue, to which was added water, was extracted three times with chloroform, whereafter the extract was washed with water, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was washed with acetone and recrystallized from acetone to obtain the product (6.79 g, yield: 66.8%).

NMR (CDCl₃, TMS) δ (ppm): 1.6-2.0 (m, 4H), 2.5-2.8 (m, 4H), 3.06 (s, 2H×2), 7.1-7.3 (s, 5H), 12.9 (br. s, 1H)

Mass (CI): 225 (M⁺ +1)

Comparative Example 16-23

2-hydroxy-3-alkyl-5,6-diethylpyrazine:

α-amino acidamide (0.20M) and 3,4-hexane (22.8 g, 020M) were added to triethylamine (200 ml), the mixture was stirred at room temperature for 30 mins. and refluxed for 15 hours. Triethylamine was distilled off in vacuo, and the residue was dissolved in chloroform and washed with dilute aqueous K₂ CO₃. The chloroform layer was dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized from acetone to obtain the products shown in Table 26.

Product, yield, (weight and %) and physical properties are shown in Table 26.

                                      TABLE 6                                      __________________________________________________________________________     1-(2-substituted ethyl)-3,5,6-trimethyl-2-oxo-1,2-dihydropyrazine                                        Starting                                                                            Heat Elution solvent                            Example                                                                             Product*                                                                            Base            Material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     2    013                                                                                  ##STR224##     026  1.75 h                                                                              20:1    1.96 78.5                          3    019                                                                                  ##STR225##     026  4    40:1    1.61 64.1                          4    020                                                                                  ##STR226##     026  1.75 20:1    1.70 64.4                          5    021                                                                                  ##STR227##     026  2    10:1    2.25 76.5                          6    022  1-imidazole     026  2    50:1    1.45 62.4                          7    023                                                                                  ##STR228##     026  5    100:1   2.42 71.2                          8    024                                                                                  ##STR229##     026  5    100:1   3.34 86.5                          9    025                                                                                  ##STR230##     026  5    100:1   3.64 97.2                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 7                                      __________________________________________________________________________     1-(2-substituted thioththyl)-3, 5, 6-trimethy-2-oxo-1, 2-dihydropyrazine                                Starting                                              Example                                                                             Product*                                                                            Mercaptane     material*                                                                           Yield (g)                                                                           Yield (%)                                   __________________________________________________________________________     10   027  HS--Ph         026  1.06 77.4                                        11   028  1-methyl-5-mercaptotetrazole                                                                  026  1.04 78.8                                        __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 8                                      __________________________________________________________________________     1-(2-substituted ethyl)-3-phenyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                  Starting                                                                            Heat Elution solvent                            Example                                                                             Product*                                                                            Base            material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     16   110                                                                                  ##STR231##     612  3    100:1   0.70 89.5                          17   111                                                                                  ##STR232##     612  3    100:1   0.99 91.0                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 9                                      __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                  Starting                                                                            Heat Elution solvent                            Example                                                                             Product*                                                                            Base            material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     20   113                                                                                  ##STR233##     613  3 h  100:1   0.78 79.5                          21   114                                                                                  ##STR234##     613  2    100:1   1.07 85.5                          22   115                                                                                  ##STR235##     613  3    100:1   0.78 57.7                          23   116                                                                                  ##STR236##     613  2    100:1   0.96 71.0                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 10                                     __________________________________________________________________________     1-(2-hydroxyethyl)-3-alkyl-5, 6-dimetyl-2-oxo-1, 2-dihydropyrazine                                   Reaction                                                                            Elution solv-                                       Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                time (hr)                                                                           ent ratio                                                                             Yield (g)                                                                           Yield (%)                               __________________________________________________________________________     24   616  Pro 3.32 g (20 mM)                                                                         2 h  100:1  3.42 81.4                                    25   622  iso-Pro                                                                            4.50 g (27 mM)                                                                         2    100:1  4.32 76.2                                    26   624  Bu  2.70 g (15 mM)                                                                         2    50:1   3.31 98.5                                    27   617  iso-Bu                                                                             5.40 g (30 mM)                                                                         2    50:1   5.12 76.2                                    28   623  sec-Bu                                                                             4.50 g (25 mM)                                                                         2    100:1  4.74 84.6                                    __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 11                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                    Starting                                                                            Heat Elution solv-                             Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ent ratio                                                                             Yield (g)                                                                           Yiled (%)                     __________________________________________________________________________     29   121                                                                                  ##STR237##      616  1.5                                                                               h 100:1  0.94 67.4                          30   122                                                                                  ##STR238##      616  2    100:1  1.00 67.9                          31   123                                                                                  ##STR239##      617  2.5  150:1  0.72 61.4                          32   124                                                                                  ##STR240##      617  2    150:1  1.41 92.3                          33   125                                                                                  ##STR241##      617  1.5  150:1  1.58 94.8                          34   126                                                                                  ##STR242##      617  1.5  150:1  1.27 76.2                          35   619                                                                                  ##STR243##      617  1.5  150:1  1.16 72.5                          36   148                                                                                  ##STR244##      622  1.5  200:1  0.94 84.2                          37   149                                                                                  ##STR245##      622  1.5  200:1  1.42 96.5                          38   150                                                                                  ##STR246##      622  2    200:1  1.41 87.6                          39   151                                                                                  ##STR247##      622  2    150:1  1.21 78.4                          40   156                                                                                  ##STR248##      624  1.5  150:1  0.85 72.5                          41   157                                                                                  ##STR249##      624  1.5  150:1  1.03 67.4                          42   158                                                                                  ##STR250##      624  1.5  150:1  1.08 64.8                          43   152                                                                                  ##STR251##      623  1    150:1  0.49 41.8                          44   153                                                                                  ##STR252##      623  1.25 150:1  0.64 41.9                          45   154                                                                                  ##STR253##      623  1.25 150:1  1.05 63.0                          46   155                                                                                  ##STR254##      623  1.5  150:1  1.12 70.0                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 12                                     __________________________________________________________________________     1-(2-hydroxyethyl)-3-alkyl-2-oxo-1, 2, 5, 6, 7, 8-hexahydro quinoxaline                              Reaction                                                                            Elution solv-                                       Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                time (hr)                                                                           ent ratio                                                                             Yield (g)                                                                           Yield (%)                               __________________________________________________________________________     47   614  Pro 6.26 g (32 mM)                                                                         1.25 h                                                                              50:1   7.15 94.7                                    48   621  Bu  5.15 g (25 mM)                                                                         2    50:1   6.15 98.4                                    49   618  iso-Bu                                                                             4.12 g (20 mM)                                                                         2    50:1   4.12 82.4                                    __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 13                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                   Starting                                                                            Heat Elution solv-                             Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ent ratio                                                                             Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     50   118                                                                                  ##STR255##      614  3  h 100:1  1.14 93.5                          51   119                                                                                  ##STR256##      614  3    100:1  1.21 95.8                          52   120                                                                                  ##STR257##      614  2.5  100:1  1.57 91.9                          53   117                                                                                  ##STR258##      614  2.5  50:1   0.70 62.2                          54   127                                                                                  ##STR259##      618  2.5  200.1  1.07 83.6                          55   128                                                                                  ##STR260##      618  1    200:1  1.58 96.8                          56   129                                                                                  ##STR261##      618  1    200:1  1.46 82.5                          57   141                                                                                  ##STR262##      621  1    200:1  0.76 59.6                          58   142                                                                                  ##STR263##      621  1    200:1  0.95 58.2                          59   143                                                                                  ##STR264##      621  2    200:1  1.49 84.2                          60   144                                                                                  ##STR265##      621  1    200:1  0.86 67.8                          61   145                                                                                  ##STR266##      621  2    50:1   0.92 63.5                          62   146                                                                                  ##STR267##      621  1.25 200:1  1.15 67.5                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 14                                     __________________________________________________________________________     1-(2-hydroxy ethyl)-3-alkyl-5, 6-diethyl-2-oxo-1, 2-dihydropyrazine                                   Reaction                                                                            Elution sol-                                       Example                                                                             Product*                                                                            Starting material (R.sub.1)                                                                 time (hr)                                                                           vent ration                                                                           Yield (g)                                                                           Yield (%)                              __________________________________________________________________________     63   620  Pro 7.76 g (40 mM)                                                                          5.5 h                                                                               50:1   6.89 73.3                                   64   625  iso-Pro                                                                            9.70 g (50 mM)                                                                          5.5  100:1  8.70 73.1                                   65   628  Bu  10.40 g (50 mM)                                                                         3    100:1  8.53 68.2                                   66   626  iso-Bu                                                                             5.20 g (25 mM)                                                                          3    100:1  5.08 81.3                                   67   627  sec-Bu                                                                             10.40 g (50 mM)                                                                         3    100:1  9.94 79.5                                   68   629  Et  4.50 g (25 mM)                                                                          2    100:1  4.38 78.2                                   __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 15                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine                                 Starting                                                                            Heat Elution Solvent                               Example                                                                             Product*                                                                            Base         material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                           Yield (%)                        __________________________________________________________________________     69   130                                                                                  ##STR268##  620  3 h  100:1   0.77 62.7                             70   131                                                                                  ##STR269##  620  1.5  200:1   1.05 66.3                             71   132                                                                                  ##STR270##  620  1.25 200:1   0.90 52.1                             72   133                                                                                  ##STR271##  620  1.5  200:1   1.02 59.0                             73   134                                                                                  ##STR272##  620  1.25 200:1   0.63 36.5                             74   159                                                                                  ##STR273##  625  1.25 200:1   0.65 52.9                             75   160                                                                                  ##STR274##  625  1.25 200:1   0.74 46.8                             76   161                                                                                  ##STR275##  625  1.25 200:1   0.99 57.5                             77   162                                                                                  ##STR276##  625  1.25 200:1   0.55 33.2                             78   163                                                                                  ##STR277##  625  1.25 200:1   0.55 45.1                             79   164                                                                                  ##STR278##  625  1.25 50:1    0.47 33.6                             80   165                                                                                  ##STR279##  625  1.25 200:1   0.77 44.7                             81   166                                                                                  ##STR280##  626  1.25 200:1   1.20 70.1                             82   167                                                                                  ##STR281##  626  1.25 200:1   0.70 54.5                             83   168                                                                                  ##STR282##  626  1.25 200:1   1.17 65.6                             84   170                                                                                  ##STR283##  626  1.25 200:1   1.31 79.9                             85   171                                                                                  ##STR284##  627  1.25 200:1   0.33 25.9                             86   172                                                                                  ##STR285##  627  2    50:1    0.30 20.6                             87   173                                                                                  ##STR286##  627  1    200:1   0.68 53.0                             88   174                                                                                  ##STR287##  627  1    200:1   0.46 28.0                             89   175                                                                                  ##STR288##  627  1.25 200:1   0.39 22.8                             90   176                                                                                  ##STR289##  627  1    200:1   0.78 43.6                             91   177                                                                                  ##STR290##  627  1.25 200:1   0.52 29.1                             92   178                                                                                  ##STR291##  628  1.25 200:1   1.08 60.8                             93   179                                                                                  ##STR292##  628  1.25 200:1   0.92 56.1                             94   180                                                                                  ##STR293##  628  1.25 200:1   1.54 86.7                             95   181                                                                                  ##STR294##  628  1    200:1   0.90 70.5                             96   182                                                                                  ##STR295##  628  1.25 200:1   0.98 76.3                             97   183                                                                                  ##STR296##  628  1.25 200:1   1.28 74.8                             98   185                                                                                  ##STR297##  628  1.25 200:1   0.78 43.9                             99   187                                                                                  ##STR298##  629  2    200:1   0.86 77.6                             100  188                                                                                  ##STR299##  629  1.25 100:1   0.80 48.1                             101  189                                                                                  ##STR300##  629  1.25 100:1   0.79 51.7                             __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 16                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-ethyl-5,6-dimethyl-2-oxo-1,2-dihydropyrazine                                    Starting                                                                            Heat Elution Solv-                             Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ent ration                                                                            Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     103  190                                                                                  ##STR301##      630  2    200:1  1.03 77.7                          104  191                                                                                  ##STR302##      630  2    200:1  1.54 79.3                          105  192                                                                                  ##STR303##      630  1.5  200:1  1.23 66.1                          106  193                                                                                  ##STR304##      630  2    200:1  1.70 88.5                          107  287                                                                                  ##STR305##      630  1    200:1  1.37 77.4                          108  288                                                                                  ##STR306##      630  1    200:1  1.42 70.6                          109  289                                                                                  ##STR307##      630  1    200:1  1.05 54.4                          110  290                                                                                  ##STR308##      630  1.5  200:1  1.39 69.7                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 17                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-5,6-diethyl-2-oxo-1,2-dihydropyrazine                                    Starting                                                                            Heat Elution solv-                             Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ent ratio                                                                             Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     112  291                                                                                  ##STR309##      640  4 h  100:1  1.15 81.0                          113  292                                                                                  ##STR310##      640  1    100:1  1.15 81.4                          114  293                                                                                  ##STR311##      640  3    100:1  1.11 62.5                          115  294                                                                                  ##STR312##      640  2    100:1  1.60 83.6                          116  295                                                                                  ##STR313##      640  2.5  100:1  0.95 46.3                          117  296                                                                                  ##STR314##      640  4    100:1  1.45 78.5                          118  297                                                                                  ##STR315##      640  2.5  100:1  0.99 52.2                          119  374                                                                                  ##STR316##      640  1    200:1  1.21 70.5                          120  375                                                                                  ##STR317##      640  1    200:1  0.99 67.4                          121  378                                                                                  ##STR318##      640  1    100:1  1.57 80.3                          122  380                                                                                  ##STR319##      640  2    200:1  0.73 42.4                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 18                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-p-chlorobenzyl-5,6-diethyl-2-oxo-1,2-dihydropyra     zine                                                                                                      Starting                                                                            Heat Elution sol-                              Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           vent ratio                                                                           Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     125  384                                                                                  ##STR320##      641  2    100:1 0.89 76.2                           126  467                                                                                  ##STR321##      641  2    100:1 1.10 76.6                           127  385                                                                                  ##STR322##      641  2    100:1 1.23 79.9                           128  386                                                                                  ##STR323##      641  2    100:1 1.15 75.4                           129  387                                                                                  ##STR324##      641  2    100:1 1.03 56.2                           __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 19                                     __________________________________________________________________________     1 - (2-hydroxyethyl) -3-alkyl-2-oxo-1, 2, 5, 6, 7, 8-hexyahydro                quinozaline                                                                    Example                                                                             Product*                                                                            Starting materil (R.sub.1)                                                                silica-gel                                                                          Elution solvent  Yield (g)                                                                           Yield (%)                      __________________________________________________________________________     130  631  --(CH.sub.2).sub.4 CH.sub.3 30 mM                                                         150 g                                                                               chloroform - methanol (200:1)                                                                   6.44 81.3                           131  632  --(CH.sub.2).sub.5 CH.sub.3 20 mM                                                         100 g                                                                               chloroform - methanol (200:1)                                                                   4.66 83.8                           132  633  --(CH.sub.2).sub.6 CH.sub.3 30 mM                                                         150 g                                                                               chloroform - methanol (200:1)                                                                   8.39 95.8                           133  634  --(CH.sub.2).sub.7 CH.sub.3 28 mM                                                         150 g                                                                               chloroform - methanol (200:1)                                                                   7.60 89.2                           134  635  --(CH.sub.2).sub.8 CH.sub.3 40 mM                                                         200 g                                                                               chloroform - methanol (200:1)                                                                   11.00                                                                               85.9                           135  636  --(CH.sub.2).sub.9 CH.sub.3 30 mM                                                         150 g                                                                               chloroform - methanol (200:1)                                                                   8.42 84.0                           136  637  --(CH.sub.2).sub.11 CH.sub.3 20 mM                                                        100 g                                                                               benzene - ethyl acetate (5:1→3:1)                                                        6.06 84.2                           137  638  --(CH.sub.2).sub.13 CH.sub.3 15 mM                                                        100 g                                                                               benzene - ethyl acetate (5:1)                                                                   3.86 66.2                           138  639  --(CH.sub.2).sub.15 CH.sub.3 20 mM                                                        100 g                                                                               benzene - ethyle acetate (5:1→3:1)                                                       5.92 70.8                           __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 20                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-alkyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                             Heat                                      Example                                                                             Product*                                                                            Starting material*                                                                       Base             time (hr)                                                                           Yield (g)                                                                           Yield (%)                       __________________________________________________________________________     139  250  631 1.06 g (4 mM)                                                                         ##STR325##      1.5 h                                                                               1.59 87.1                            140  251  631 1.06 g (4 mM)                                                                         ##STR326##      2    1.65 93.8                            141  252  631 1.32 g (5 mM)                                                                         ##STR327##      1.5  1.05 63.1                            142  253  631 1.06 g (4 mM)                                                                         ##STR328##      2    1.01 65.1                            143  254  631 1.06 g (4 mM)                                                                         ##STR329##      1.5  1.35 74.7                            144  255  632 1.25 g (4.5 mM)                                                                       ##STR330##      2    1.34 85.8                            145  256  632 0.95 g (3.5 mM)                                                                       ##STR331##      2    0.88 53.4                            146  257  632 0.95 g (3.5 mM)                                                                       ##STR332##      2    1.50 89.1                            147  258  632 1.12 g (4 mM)                                                                         ##STR333##      2    1.44 76.9                            148  305  632 1.12 g (4 mM)                                                                         ##STR334##      2    1.38 81.7                            149  306  632 1.12 g (4 mM)                                                                         ##STR335##      2    1.32 75.7                            150  307  632 1.12 g (4 mM)                                                                         ##STR336##      2    1.49 83.9                            151  308  632 1.12 g (4 mM)                                                                         ##STR337##      2    1.73 92.8                            152  309  632 1.12 g (4 mM)                                                                         ##STR338##      2.5  1.38 75.6                            153  310  632 1.12 g (4 mM)                                                                         ##STR339##      2.5  1.43 79.1                            154  311  632 1.12 g (4 mM)                                                                         ##STR340##      2.5  1.44 72.7                            155  312  632 1.12 g (4 mM)                                                                         ##STR341##      2    1.49 76.9                            156  313  632 1.12 g (4 mM)                                                                         ##STR342##      2    0.81 42.2                            157  259  633 1.17 g (4 mM)                                                                         ##STR343##      2    0.94 65.1                            158  260  633 1.17 g (4 mM)                                                                         ##STR344##      2    1.03 53.4                            159  261  633 1.17 g (4 mM)                                                                         ##STR345##      2    1.50 75.8                            160  262  633 1.17 g (4 mM)                                                                         ##STR346##      2    1.28 68.4                            161  263  633 1.17 g (4 mM)                                                                         ##STR347##      2    0.85 51.1                            162  264  633 1.17 g (4 mM)                                                                         ##STR348##      2    1.42 71.4                            163  314  633 1.17 g (4 mM)                                                                         ##STR349##      2    1.50 83.3                            164  315  633 1.17 g (4 mM)                                                                         ##STR350##      2    0.44 25.2                            165  316  633 1.17 g (4 mM)                                                                         ##STR351##      2    1.70 93.3                            166  317  633 1.17 g (4 mM)                                                                         ##STR352##      2    1.30 69.1                            167  318  633 1.17 g (4 mM)                                                                         ##STR353##      2.5  1.11 57.6                            168  319  633 1.17 g (4 mM)                                                                         ##STR354##      2    1.01 51.1                            169  320  633 1.17 g (4 mM)                                                                         ##STR355##      1.5  1.29 63.4                            170  265  634 1.23 g (4 mM)                                                                         ##STR356##      2    1.01 67.3                            171  266  634 0.92 g (3 mM)                                                                         ##STR357##      2    1.49 99.6                            172  267  634 0.92 g (3 mM)                                                                         ##STR358##      2    1.24 83.7                            173  268  634 0.92 g (3 mM)                                                                         ##STR359##      2    1.40 91.7                            174  269  634 0.92 g (3 mM)                                                                         ##STR360##      2    1.27 87.8                            175  270  634 1.23 g (4 mM)                                                                         ##STR361##      2    1.18 59.5                            176  321  634 1.23 g (4 mM)                                                                         ##STR362##      2    1.79 96.4                            177  322  634 1.23 g (4 mM)                                                                         ##STR363##      2    1.58 87.8                            178  323  634 1.23 g (4 mM)                                                                         ##STR364##      3    1.90 99.0                            179  324  634 1.23 g (4 mM)                                                                         ##STR365##      2    1.54 79.5                            180  325  634 1.23 g (4 mM)                                                                         ##STR366##      2    1.45 69.3                            181  326  634 1.23 g (4 mM)                                                                         ##STR367##      2    1.33 65.5                            182  327  634 1.23 g (4 mM)                                                                         ##STR368##      2    1.41 68.8                            183  271  635 1.28 g (4 mM)                                                                         ##STR369##      2    1.03 66.2                            184  272  635 0.96 g (3 mM)                                                                         ##STR370##      2    1.15 74.8                            185  273  635 0.96 g (3 mM)                                                                         ##STR371##      2    1.25 84.0                            186  274  635 0.96 g (3 mM)                                                                         ##STR372##      2    1.15 73.3                            187  275  635 0.96 g (3 mM)                                                                         ##STR373##      2    0.72 47.2                            188  328  635 0.96 g (3 mM)                                                                         ##STR374##      2    1.30 90.7                            189  329  635 0.96 g (3 mM)                                                                         ##STR375##      2    0.87 55.1                            190  330  635 0.96 g (3 mM)                                                                         ##STR376##      2.5  1.08 67.0                            191  331  635 0.96 g (3 mM)                                                                         ##STR377##      2    0.61 39.9                            192  332  635 0.96 g (3 mM)                                                                         ##STR378##      2    1.04 66.4                            193  334  636 1.01 g (3 mM)                                                                         ##STR379##      2    0.96 79.4                            194  335  636 1.01 g (3 mM)                                                                         ##STR380##      2    1.28 86.6                            195  336  636 1.01 g (3 mM)                                                                         ##STR381##      2    0.91 63.5                            196  337  636 1.01 g (3 mM)                                                                         ##STR382##      2.5  1.38 88.1                            197  338  636 1.01 g (3 mM)                                                                         ##STR383##      2    1.32 83.6                            198  339  636 1.01 g (3 mM)                                                                         ##STR384##      3    1.48 89.5                            199  340  636 1.01 g (3 mM)                                                                         ##STR385##      2    1.24                                 200  276  637 1.09 g (3 mM)                                                                         ##STR386##      2    1.16 89.5                            201  277  637 1.09 g (3 mM)                                                                         ##STR387##      2    1.27 76.3                            202  278  637 1.09 g (3 mM)                                                                         ##STR388##      2    0.60 36.2                            203  279  637 1.09 g (3 mM)                                                                         ##STR389##      2    1.35 79.6                            204  280  638 1.17 g (3 mM)                                                                         ##STR390##      2    0.91 66.1                            205  281  638 1.17 g (3 mM)                                                                         ##STR391##      2    1.21 69.8                            206  282  638 1.17 g (3 mM)                                                                         ##STR392##      2    0.97 55.7                            207  487  638 1.17 g (3 mM)                                                                         ##STR393##      2    1.43 87.0                            208  488  638 1.17 g (3 mM)                                                                         ##STR394##      3    0.89 48.9                            209  489  638 1.17 g (3 mM)                                                                         ##STR395##      3    0.92 51.4                            210  490  638 1.17 g (3 mM)                                                                         ##STR396##      2.5  0.98 55.2                            211  283  639 1.26 g (3 mM)                                                                         ##STR397##      2    1.22 83.5                            212  284  639 1.26 g (3 mM)                                                                         ##STR398##      2    1.52 83.0                            213  285  639 1.26 g (3 mM)                                                                         ##STR399##      2    1.77 95.0                            214  286  639 1.26 g (3 mM)                                                                         ##STR400##      2    1.76 93.9                            __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 2                                      __________________________________________________________________________     1-[ 2-(4'-acylpiperadinyl) ethyl]-3-ethyl-5, 6-dimethyl-2-oxo-1,               2-dihydropyrazine                                                                        Acylation               Reaction                                                                            Elution sol-                            Example                                                                             Product*                                                                            Method     Acylating agent                                                                             time vent ratio                                                                            Yield (g)                                                                           Yield                       __________________________________________________________________________                                                        (%)                         216  455  acid chloride                                                                             ClCO--CH.sub.2 Ph                                                                           1 h  100:1  0.93 81.2                        217  457  acid anhydride                                                                            2-thienylchloride                                                                           4    100:1  1.35 87.0                        218  459  acid anhydride                                                                            HOOC--CH.sub.2 Ph-NO.sub.2 (p)                                                              5    200:1  0.98 57.4                        219  465  acid chloride                                                                             ClSO.sub.2 --Ph-Cl (p)                                                                      1    200:1  1.23 93.5                        220  456  acid anhydride                                                                            HOOC--Ph-Cl (p)                                                                             2    100:1  1.49 92.5                        221  458  acid anhydride                                                                            HOOC--Ph-NO.sub.2 (p)                                                                       2    100:1  1.59 96.2                        222  460  acid chloride                                                                             HOOC--Ph-OMe (p)                                                                            1    100:1  1.07 89.6                        223  461  acid anhydride                                                                            HOOC--Ph-OMe.sub.2 (2, 3)                                                                   2    100:1  1.56 91.1                        224  462  acid anhydride                                                                            HOOC--Ph-OMe.sub.2 (2, 4)                                                                   2    200:1  1.51 88.2                        225  463  acid anhydride                                                                            HOOC--Ph-OMe.sub.2 (3, 4)                                                                   4    100:1  1.55 90.5                        226  464  acid anhydride                                                                            HOOC--Ph-OMe.sub.3 (3, 4, 5)                                                                3    100:1  1.40 99.0                        __________________________________________________________________________      *; Compound No.                                                          

                                      TABLE 22                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-benzyl-2-oxo-1,2,5,6,7,8-hexahydro quinoxaline                                   Starting                                                                            Heat Elution solvent                          Compound                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           ratio   Yield (g)                                                                            Yield                      __________________________________________________________________________                                                         (%)                        229   470                                                                                  ##STR401##      643  3 h  100:1   0.67  52.6                       230   471                                                                                  ##STR402##      643  3    100:1   1.01  62.3                       231   472                                                                                  ##STR403##      643  3    200:1   0.82  54.7                       232   473                                                                                  ##STR404##      643  3    200:1   1.10  66.0                       233   474                                                                                  ##STR405##      643  2.5  100:1   0.93  56.3                       234   475                                                                                  ##STR406##      643  2.75 100:1   1.15  71.4                       __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 23                                     __________________________________________________________________________     1-(2-subsituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydro           quinoxaline                                                                                               Starting                                                                            Heat Elution sol-                              Example                                                                             product*                                                                            Base             material*                                                                           time (hr)                                                                           vent ratio                                                                            Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     237  476                                                                                  ##STR407##      645  2 h  100:1  1.07 83.3                          238  477                                                                                  ##STR408##      645  2    100:1  1.35 84.6                          239  478                                                                                  ##STR409##      645  2    200:1  1.01 65.2                          240  479                                                                                  ##STR410##      645  2.5  100:1  1.41 82.0                          241  480                                                                                  ##STR411##      645  2.5  100:1  0.98 57.6                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 24                                     __________________________________________________________________________     1-(2-substituted ethyl)-3-(2-phenylethyl)-2-oxo-1,2,5,6,7,8-hexahydro          quinoxaline                                                                                               Starting                                                                            Heat Elution sol-                              Example                                                                             Product*                                                                            Base             material*                                                                           time (hr)                                                                           vent ratio                                                                            Yield (g)                                                                           Yield (%)                     __________________________________________________________________________     243  481                                                                                  ##STR412##      646  2.5 h                                                                               100:1  0.98 62.6                          244  482                                                                                  ##STR413##      646  2.5  100:1  1.54 74.3                          245  483                                                                                  ##STR414##      646  2    100:1  1.67 87.9                          246  484                                                                                  ##STR415##      646  2.5  200:1  1.29 70.5                          247  485                                                                                  ##STR416##      646  2    100:1  1.25 58.3                          248  486                                                                                  ##STR417##      646  3    100:1  1.78 86.8                          __________________________________________________________________________      *Compound No.                                                            

                                      TABLE 25                                     __________________________________________________________________________     2-hydroxy-3-alkyl-5,6,7,8-tetrahydro quinoxaline                                ##STR418##                                                                    Comp.       Yield                                                                              Yield                                                          Exa.                                                                               Product (R.sub.1)                                                                      (g) (%) NMR (CDCl.sub.3) δ (ppm)                                                                            Mass                            __________________________________________________________________________     3   Bu      7.49                                                                               73.0                                                                               0.94(t, 3H, butyl 4-CH.sub.3), 1.24˜2.00(m,                              butyl 2-CH.sub.2,          207 (M.sup.+ + 1)                                   3-CH.sub.2, quinoxaline 6-H.sub.2, 7-H.sub.2),                                 2.55˜2.85 (m, 6H, butyl                                                  1-CH.sub.2, quinoxaline 5-H.sub.2, 8-H.sub.2), 12.99                           (br. s, 1H, OH)                                            4   iso-Bu  6.58                                                                               64.0                                                                               0.96 (d, 6H, isobutyl 2 × CH.sub.3),                                     1.6˜2.0 (m, 4H, 6-H.sub.2, 7-                                                                       207 (M.sup.+ + 1)                                   H.sub.2), 2.0˜2.4 (isobutyl CH), 2.5˜2.8                           (m, 6H, 5-H.sub.2, 8-                                                          H.sub.2)                                                   5   (CH.sub.2).sub.4 CH.sub.3                                                              9.03                                                                               82.0                                                                               0.90 (t, 3H, J ≈ 6.3), 1.2˜1.5 (m, 4H),                          1.5˜1.9 (m, 6H       221 (M.sup.+ + 1)                                   ), 2.5˜2.9 (m, 6H)   164                             6   (CH.sub.2).sub.5 CH.sub.3                                                              7.81                                                                               66.7                                                                               0.88 (t, 3H, J ≈ 7.9), 1.1˜1.5 (m, 6H),                          1.5˜2.0 (m, 6H       235 (M.sup.+ + 1)                                   ), 2.4˜2.9 (m, 6H)                                   7   (CH.sub.2).sub.5 CH.sub.3                                                              9.33                                                                               75.0                                                                               0.88 (t, 3H, J ≈ 7.4), 1.1˜1.5 (m, 8H),                          1.5˜2.0 (m, 6H       249 (M.sup.+ + 1)                                   ), 2.5˜2.9 (m, 6H)                                   8   (CH.sub.2).sub.7 CH.sub.3                                                              11.67                                                                              89.1                                                                               0.88 (t, 3H, J ≈ 7.5), 1.1˜1.5 (m,                               10H), 1.5˜2.0 (m, 6  263 (M.sup.+ + 1)                                   H), 2.5˜2.9 (m, 6H)                                  9   (CH.sub.2).sub.8 CH.sub.3                                                              12.73                                                                              92.2                                                                               0.88 (t, 3H, J ≈ 6.2), 1.1˜1.5 (m,                               12H), 1.5˜2.0 (m, 6  277 (M.sup.+ + 1)                                   H), 2.5˜2.8 (m, 6H)  164                             10  (CH.sub.2).sub.9 CH.sub.3                                                              10.46                                                                              72.4                                                                               0.88 (t, 3H, J ≈ 6.0), 1.2˜2.0 (m,                               20H), 2.5˜2.9 (m, 6  291 (M.sup.+ + 1)                                   H), 12.7 (br. s, 1H)                                       11  (CH.sub.2).sub.11 CH.sub.3                                                             14.00                                                                              88.1                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 24H),                           2.4˜2.8 (m, 6H)      319 (M.sup.+ + 1)                                                              164                             12  (CH.sub.2).sub.13 CH.sub.3                                                             16.58                                                                              95.8                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 28H),                           2.4˜2.8 (m, 6H)      347 (M.sup.+ + 1)                                                              164                             13  (CH.sub.2).sub.15 CH.sub.3                                                             18.55                                                                              99.2                                                                               0.88 (t, 3H, J ≈ 6), 1.1˜1.9 (m, 32H),                           2.5˜2.8 (m, 6H)      375 (M.sup.+ + 1)                                                              164                             __________________________________________________________________________

                                      TABLE 26                                     __________________________________________________________________________      ##STR419##                                                                    Comp.       Yield                                                                              Yield                                                          Exa.                                                                               Product (R.sub.1)                                                                      (g) (%) NMR (CDCl.sub.3) δ (ppm)                                                                         Mass                               __________________________________________________________________________     16  Et      14.4                                                                               40  1.1˜1.4 (m, 9H), 2.3˜3.0 (m, 6H), 13.2                             (br. s, 1H)             167                                17  Pro     16.5                                                                               43  1.00 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H),                                      1.5˜1.9 (m,       181                                                    2H), 2.47 (q, 2H), 2.54 (q, 2H), 2.76 (q, 2H), 13.1 (                          br. s, 1H)                                                 18  iso-Pro 18.2                                                                               47  1.0˜1.4 (m, 12H), 2.56 (q, 2H), 2.58 (q, 2H),                            3.40 (                  195                                                    sept, 1H), 12.9 (br. s, 1H)                                19  Bu      17.5                                                                               42  0.95 (t, 3H), 1.19 (t, 3H), 1.27 (t, 3H),                                      1.2˜1.9 (m,       209                                                    4H), 2.57 (q, 2H×2), 2.73 (t, 3H), 12.9 (br. s,                          1H)                                                        20  iso-Bu  16.5                                                                               40  0.96 (t, 3H), 1.19 (t, 3H), 1.28 (t, 3H),                                      1.9˜2.4 (m,       209                                                    H), 2.41 (q, 2H), 2.58 (q, 2H), 2.66 (d, 2H), 13.0 (                           br. s, 1H)                                                 21  sec-Bu  17.5                                                                               42  0.88 (t, 3H×2), 1.0˜1.4 (m, 9H),                                   1.4˜2.0 (m, 2H), 2.                                                                              209                                                    46 (q, 2H), 2.57 (q, 2H), 12.8 (br. s, 1H)                 22  CH.sub.2 Ph                                                                            27.9                                                                               57.6                                                                               1.19 (t, 3H, J≈7.6), 1.23 (t, 3H,                                      J≈7.6), 2.50 (q, 2H                                                                            243                                                    J≈7.6), 2.53 (q, 2H, J≈7.6), 4.07 (s,                          2H), 7.0˜7.4                                                             (m, 5H), 13.2 (br. s, 1H)                                  23  CH.sub.2 PhCl                                                                          27.4                                                                               49.6                                                                               1.19 (t, 3H, J≈7.7), 1.23 (t, 3H,                                      J≈7.7), 2.53 (q, 2H                                                                            279                                    (p)             J≈7.7), 2.57 (q, 2H, J≈7.7), 4.03 (s,                          2H), 7.0˜7.4      277                                                    (m, 4H), 13.3 (br. s, 1H)                                  __________________________________________________________________________

                                      TABLE 27                                     __________________________________________________________________________     Compound Nos.                                                                           NMR (CDCl.sub.3, TMS) δ             Mass    TLC                 __________________________________________________________________________     018      1.3-1.8(6H,m), 2.30(3H,s), 2.38(3H,s), 2.41(3H,s),                             2.5-2.8(6H,m), 4.1-4.3(2H,m)              250(M.sup.+ +1)                                                                        0.25                019      2.31(3H,s), 2.34(3H,s), 2.41(3H,s), 2.5-2.7(6H,m),                             3.6-3.8(4H,m), 4.0-4.2(2H,m)              252(M.sup.+ +1)                                                                        0.31                020      2.29(3H×2,s), 2.34(3H,s), 2.41(3H,s), 2.3-2.9(10H,m),                    4.0-4.2(2H,m)                             265(M.sup.+ +1)                                                                        0.10                021      2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.4-2.7(12H,m), 2.92(1H,s),                2.63(2H,t,J≈                      295(M.sup.+ +1)                                                                        0.08                         5.4), 4.0-4.2(2H,m)                                                   022      1.79(3H,s), 2.24(3H,s), 2.45(3H,s), 4.2-4.4(4H,m),                             6.7-6.8(1H,m), 7.0-7.1(1H,m)              233(M.sup.+ +1)                                                                        0.30                         7.2-7.4(1H,m)                                                         023      2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.54(2H,s),                4.0-4.2(2H,m),                            341(M.sup.+ +1)                                                                        0.35                         7.30(5H,s)                                                            024      2.30(3H,s), 2.33(3H,s), 2.41(3H,s), 2.3-2.7(10H,m), 3.47(2H,s),                4.0-4.2(2H,m),                            375 377 0.36                         7.24(4H,s)                                (M.sup.+ +1)                025      2.30(3H,s), 2.34(3H,s), 2.41(3H,s), 2.57(8H,s), 2.5-2.7(2H,m),                 3.62(2H,s), 4.0-                          375 377 0.36                         4.2(2H,m), 7.1-7.5(4H,m)                  (M.sup.+ +1)                026      2.29(3H,s), 2.35(3H,s), 2.38(3H,s), 3.4(1H,bs), 3.8-4.0(2H,m),                 4.1-4.3(2H,s)                             183(M.sup.+ +1)                                                                        0.26                027      2.21(3H,s), 2.25(3H,s), 2.38(3H,s), 3.1-3.3(2H,m),                             4.1-4.3(2H,m), 7.1-7.6(5H,m)              275(M.sup.+ +1)                                                                        0.48                028      2.32(3H,s), 2.43(3H,s), 2.46(3H,s), 3.4-3.7(2H,m), 3.95(3H,s)                  4.3-4.6(2H,m)                             281(M.sup.+ +1)                                                                        0.39                061      2.06(3H,s), 2.32(3H,s), 2.34(3H,s), 2.42(3H,s),                                4.31(2H,t,J≈3.3), 4.33(2H,t,J≈                                                                           225(M.sup.+ +1)                                                                        0.31                         3.3)                                                                  062      2.31(3H×2,s), 2.41(3H,s), 2.79(3H,d,J=5.4), 4.1-4.4(4H,m),               4.8-5.0(1H,bm)                            240(M.sup.+ +1)                                                                        0.31                063      2.21(3H,s), 2.25(3H,s), 2.31(3H,s), 4.1-4.4(4H,m),                             4.8-5.0(1H,b), 6.9-7.5(5H,m)              302(M.sup.+ +1)                                                                        0.41                064      2.20(3H,s), 2.25(3H,s), 2.31(3H,s), 4.2-4.4(4H,m),                             4.8-5.0(1H,b), 7.1-7.5(4H,m)              338(M.sup.+ +1)                                                                        0.42                                                                   336                         101      2.30(3H×2,s), 2.33(3H×2,s), 2.58(3H×2,s),                    2.58(8H,s), 2.5-2.7(4H,m), 4.0-4.2(       415(M.sup.+ +1)                                                                        0.13                         4H,m)                                                                 109      2.38(3H,s), 2.41(3H,s), 3.97(2H,t,J≈5.2),                              4.25(2H,t,J≈5.2), 7.2-7.5(3H,m), 8.1-                                                                            265(M.sup.+ +1)                                                                        0.34                         8.2(2H,m)                                                             110      2.42(3H×2,s), 2.4-2.8(6H,m), 3.6-3.8(4H,m),                              4.25(2H,t,J≈6.9), 7.3-7.5(3H,m),  314(M.sup.+ +1)                                                                        0.40                         8.1-8.3(2H,m)                             227                         111      2.41(3H×2,s), 2.3-2.8(10H,m), 3.46(2H,s),                                4.23(2H,t,J≈6.1), 7.27(4H,s), 7.2-                                                                               441 439 0.40                         7.4(2H,m), 8.1-8.3(2H,m)                  (M.sup.+ +1)                112      2.32(3H×2,s), 3.90(2H,t,J=5.3), 4.08(2H,s),                              4.20(2H,t,J=5.3), 7.1-7.5(5H,m)           258(M.sup.+ +1)                                                                        0.34                113      2.31(3H×2,s), 2.4-2.7(6H,m), 3.5-3.7(4H,m), 4.08(2H,s),                  4.0-4.2(2H,m), 7.1-7.5                    328(M.sup.+ +1)                                                                        0.35                         (5H,m)                                    241                                                                            114                         114      2.30(3H×2,s), 2.3-2.7(10H,m), 3.51(2H,s), 4.08(2H,s),                    3.9-4.2(2H,m), 7.1-7.4(                   417(M.sup.+ +1)                                                                        0.32                         10H,m)                                                                115      2.30(3H×2,s), 2.3-2.7(10H,m), 3.45(2H,s), 4.08(2H,s),                    3.9-4.2(2H,m), 7.1-7.4(                   452(M.sup.+ +1)                                                                        0.35                         9H,m)                                     450                                                                            223                         116      2.31(3H×2,s), 2.4-2.7(10H,m), 3.62(2H,s), 4.08(2H,s),                    4.0-4.2(2H,m), 7.1-7.9(                   452(M.sup.+ +1)                                                                        0.38                         9H,m)                                     450                                                                            223                         117      0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.0-2.3(2H,m), 2.4-2.8(16H,m),                3.5-3.7(2H,m),                            349(M.sup.+ +1)                                                                        0.08                         3.9-4.2(2H,m)                                                         118      0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.4-2.9(12H,m), 3.5-3.8(4H,m),                3.9-4.2(2H,m)                             306(M.sup.+ +1)                                                                        0.43                                                                   219                                                                            214                         119      0.98(3H,t,J≈7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m),                       3.51(2H,s), 3.9-4.2(2H,m),                395(M.sup.+ +1)                                                                        0.40                         7.29(5H,s)                                189                         120      0.99(3H,t,J=7.3), 1.7-2.0(6H,m), 2.3-2.9(16H,m), 3.47(2H,s),                   3.9-4.2(2H,m),                            429(M.sup.+ +1)                                                                        0.38                         7.26(4H,s)                                431                         121      0.99(3H,t,J=7.3), 1.5-1.9(2H,m), 2.31(3H,s), 2.33(3H,s),                       2.4-2.8(8H,m), 3.6-                       280(M.sup.+ +1)                                                                        0.33                         3.8(4H,m), 4.0-4.3(2H,m)                  193                         122      0.98(3H,t,J=7.3), 1.5-1.9(2H,m), 2.30(2H×3,s),                           2.4-2.8(12H,m), 3.51(2H,s),               369(M.sup.+ +1)                                                                        0.22                         4.0-4.2(2H,m), 7.29(5H,s)                 193                         123      0.94(3H×2,d,J=6.6), 1,9-2.4(1H,m), 2.31(3H,s), 2.33(3H,s),               2.4-2.7(8H,m), 3.6-                       294(M.sup.+                                                                            0.40                         3.8(4H,m), 4.0-4.3(2H,m)                  207                                                                            114                                                                            102                         124      0.93(3H×2,d,J=6.6), 1.9-2.4(1H,m), 2.17(3H,s), 2.31(3H,s),               2.4-2.7(12H,m), 3.51                      383(M.sup.+ +1)                                                                        0.31                         (2H,s), 4.0-4.3(2H,m), 7.30(5H,s)         207                         125      0.93(3H×2,d,J=6.6), 1.9-2.4(1H,m), 2.31(3H×2,s),                   2.3-2.8(12H,m), 3.46(2H,s),               419(M.sup.+ +1)                                                                        0.29                         4.0-4.3(2H,m), 7.26(4H,s)                 417                                                                            207                                                                            125                         126      0.94(3H×2,d,J=6.6), 1,9-2.4(1H,m), 2.31(3H×2,s),                   2.3-2.8(12H,m), 3.47(2H,s),               419(M.sup.+ +1)                                                                        0.31                         4.0-4.3(2H,m), 7.26(4H,s)                 417                                                                            207                                                                            125                         127      0.95(3H×2,d,J=6.6), 1.7-1.9(4H,m), 2.0--2.2(1H,m),                       2.5-2.8(12H,m), 3.6-3.8(4H,               320(M.sup.+ +1)                                                                        0.39                         m), 4.0-4.2(2H,m)                         233                                                                            114                                                                            102                         128      0.94(3H×2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m),                        2.3-2.8(16H,m), 3.51(2H,s),               409(M.sup.+ +1)                                                                        0.38                         3,9-4.2(2H,m), 7.29(5H,s)                 233                                                                            189                         129      0.94(3H,d,J=6.4), 0.96(3H,d,J=6.4), 1.6-2.0(4H,m),                             2.0-2.4(1H,m), 2.3-2.8(16H,               445(M.sup.+ +1)                                                                        0.37                         m), 7.45(2H,s), 3.8-4.3(2H,m), 7.26(4H,s) 443                                                                            233                                                                            125                         130      0.99(3H,t,J=7.3), 1.21(3H,t,J=7.6), 1.23(2H,t,J=7.6),                          1.5-2.0(2H,m), 2.4-2.9                    308(M.sup.+ +1)                                                                        0.37                         (12H,m), 3.6-3.8(4H,m), 4.0- 4.3(2H,m)    221                                                                            102                         131      0.99(3H,t,J=7.2), 1.20(3H,t,J=7.5), 1.4-1.9(2H,m), 2.2-                        2.8(16H,m), 3.51(2H,                      397(M.sup.+ +1)                                                                        0.38                         s), 3,8-4.3(2H,m), 7.29(5H,s)             221                         132      0.99(3H,t,J=7.2), 1.21(3H×2,t.J=7.6), 1.5-2.0(2H,m),                     2.3-2.9(16H,m), 3.48(2H,                  433(M.sup.+ +1)                                                                        0.31                         s), 3.9-4.3(2H,m), 7.26(4H,s)             431                                                                            307                                                                            221                                                                            125                         133      0.99(3H,t,J=7.2), 1.20(3H×2,t,J=7.6), 1.4-2.1(2H,m),                     2.3-2.9(16H,m), 3.48(2H,                  433(M.sup.+ +1)                                                                        0.28                         s), 4.0-4.3(2H,m), 7.1-7.4(4H,m)          431                                                                            239                                                                            221                                                                            125                         134      0.99(3H,t,J=7.8), 1.20(3H,t,J=7.6), 1.21(3H,t,J=7.6),                          1.4-2.1(2H,m), 2.4-2.9(                   433(M.sup.+ +1)                                                                        0.32                         16H,m), 2.64(2H,s), 4.0-4.3(2H,m), 7.1-7.5(4H,m)                                                                         431                                                                            221                                                                            125                         141      0.94(3H,t,J=6.4), 1.2-2.0(8H,m), 2.4-2.9(12H,m), 3.6-3.8(4H,m),                3.9-4.2(2H,m)                             320(M.sup.+ +1)                                                                        0.44                142      0.93(3H,t,J≈6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m),                       3.51(2H,s), 3.9-4.3(2H,m),                409(M.sup.+ +1)                                                                        0.47                         7.29(5H,s)                                189                         143      0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s),                   3.9-4.2(2H,m),                            445(M.sup.+ +1)                                                                        0.46                         7.26(4H,s)                                443                                                                            225                                                                            223                                                                            125                         144      0.93(3H,t,J=6.4), 1.2-2.0(14H,m), 2.4-2.9(12H,m),                                                                        318(M.sup.+                                                                            0.33                                                                   223                                                                            111                         145      0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.0-2.9(16H,m),                               3.61(2H,t,J=5.2), 3,9-4.2(2H,m)           363(M.sup.+ +1)                                                                        0.09                                                                   143                                                                            125                         146      0.93(3H,t,J=6.4), 1.2-2.0(8H,m), 2.3-2.9(16H,m), 3.46(2H,s),                   3.9-4.2(2H,m),                            427(M.sup.+ +1)                                                                        0.42                         6.8-7.1(2H,m), 7.1-7.3(2H,m)              207                         148      1.21(3H×2,d,J=6.0), 2.32(3H×2,s), 2.4-2.7(6H,m),                   3.42(1H,sept,J=6.9), 3.6-3.8              280(M.sup.+ +1)                                                                        0.40                         (2H,m), 3.8-4.4(4H,m)                     114                         149      1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                           369(M.sup.+ +1)                                                                        0.39                         3.42(1H,sept,J=6.9), 3.52(2H,s), 3.9-4.2(2H,m),                                                                          2049(5H,s)                  150      1.23(3H,s,J=6.9), 1.25(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                           405(M.sup.+ +1)                                                                        0.38                         3.42(1H,sept,J=6.9), 3.46(2H,s), 3.8-4.3(2H,m),                                                                          4036(4H,s)                                                                     223                         151      1.23(3H,d,J=6.9), 1.24(3H,d,J=6.9), 2.30(3H,s), 2.32(3H,s),                    2.3-2.7(10H,m),                           413(M.sup.+ +1)                                                                        0.39                         3.42(1H,sept,J=6.9), 3.47(2H,s), 3.9-4.2(2H,m), 6.8-7.1(2H,m),                 7.1-7.3(2H,m)                                                         152      0.88(3H,t,J=7.4), 1.11(3H,d,J=6.9), 1.3-2.0(2H,m),                             2.32(3H×2,s), 2.4-2.8(8H,m)         294(M.sup.+ +1)                                                                        0.44                         3.0-3.5(1H,m), 3.6-3.8(4H,m), 4.0-4.4(2H,m)                                                                              114                                                                            102                         153      0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m), 2.30(3H,s),                 2.32(3H,s),                               383(M.sup.+ +1)                                                                        0.38                         2.3-2.7(10H,m), 3.0-3.4(1H,m), 3.51(2H,s), 3.8- 4.3(2H,m),                     7.29(5H,s)                                189                         154      0.88(3H,t,J=7.4), 1.17(3H,d,J=6.9), 1.2-2.0(2H,m),                             2.31(3H×2,s), 2.3-2.7(10H,          419(M.sup.+ +1)                                                                        0.34                         m), 3.0-3.5(1H,m), 3.47(2H,s), 3.8-4.3(2H,m), 7.26(4H,s)                                                                 417                                                                            223                         155      0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.3-2.0(2H,m),                             2.31(3H×2,s), 2.3-2.7(10H,          401(M.sup.+ +1)                                                                        0.36                         m), 3.0-3.5(1H,m), 3.47(2H,s), 4.0-4.3(2H,m), 7.1-7.3(2H,m)                                                              207                         156      0.94(3H,t,J=6.7), 1.2-1.8(4H,m), 2.31(3H,s), 2.33(3H,s),                       2.3-2.9(8H,m), 3.6-3.8                    294(M.sup.+ +1)                                                                        0.42                         (4H,m), 4.0-4.3(2H,m)                     207                                                                            114                                                                            102                         157      0.93(3H,t,J=6.7), 1.2-1.9(4H,m), 2.30(3H,s), 2.33(3H,s),                       2.3-2.9(12H,m), 3.51                      383(M.sup.+ +1)                                                                        0.41                         (2H,s), 3.9-4.2(2H,m), 7.29(5H,s)         207                         158      0.93(3H,t,J=6.7), 1.2-1.8(4H,m), 2.30(3H,s), 2.32(3H,s),                       2.3-2.9(12H,m), 3.47                      419(M.sup.+ +1)                                                                        0.46                         (2H,s), 3.9-4.3(2H,m), 7.26(4H,s)         417                                                                            207                                                                            125                         159      1.1-1.4(12H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8),                           3.8-4.4(6H,m)                             308(M.sup.+ +1)                                                                        0.47                                                                   239                                                                            113                         160      1.1-1.4(12H,m), 2.3-2.8(14H,m), 3.41(1H,sept,J=6.9), 3.52(2H,s),               3.8-4.3(2H,m),                            396(M.sup.+ +1)                                                                        0.49                         7.29(5H,s)                                189                         161      1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s),               3.8-4.3(2H,m),                            433(M.sup.+ +1)                                                                        0.48                         7.26(4H,s)                                431                                                                            236                                                                            223                                                                            125                         162      1.20(3H×2,t,J=7.3), 1.21(3H×2,d,J=6.8)                             2.4-2.8(14H,m), 3.41(1H,sept,J=6.8),      415(M.sup.+ +1)                                                                        0.43                         3.48(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m)                                                                  207                         163      1.0-1.7(18H,m), 2.4-2.8(10H,m), 3.42(1H,sept,J=6.8),                           3.8-4.3(2H,m)                             306(M.sup.+ +1)                                                                        0.44                                                                   239                                                                            221                         164      1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.41(1H,sept,J=6.8), 3.48(2H,s),               3.9-4.3(2H,m),                            415(M.sup.+ +1)                                                                        0.13                         6.8-7.1(2H,m), 7.1-7.3(2H,m)              207                         165      1.1-1.4(12H,m), 2.4-2.8(14H,m), 3.42(1H,sept,J=6.8), 3.48(2H,s),               3.8-4.3(2H,m),                            433(M.sup.+ +1)                                                                        0.40                         7.1-7.3(4H,m)                             431                                                                            223                         166      0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.4),                          1.21(3H,t,J=7.4), 2.4-2.5                 429(M.sup.+ +1)                                                                        0.46                         (1H,sept,J=6.7), 2.3-2.9(16H,m), 3.48(2H,s), 3.8-4.3(2H,m),                    6.8-7.1(2H,m), 7.1-                       220                                  7.4(2H,m)                                 207                         167      0.95(3H×2,d,J=6.4), 1.21(3H×2,t,J=7.4),                            2.0-2.4(1H,m), 2.4-2.8(12H,m), 3.5-3.8    322(M.sup.+ +1)                                                                        0.41                         (4H,m), 4.0-4.3(2H,m)                                                 168      0.94(3H,d,J=6.7), 0.95(3H,d,J=6.7), 1.20(3H,t,J=7.3),                          1.21(3H,t,J=7.3), 2.0-2.5                 447(M.sup.+ +1)                                                                        0.44                         (1H,m), 2.3-2.9(16H,m), 3.47(2H,s), 3.9-4.3(2H,m),                                                                       4456(4H,s)                                                                     223                         170      0.94(3H×2,d,J=6.7), 1.20(3H,t,J=6.7), 1.21(3H,t,J=6.5),                  2.0-2.4(1H,m), 2.3-2.8                    411(M.sup.+ +1)                                                                        0.36                         (16H,m), 3.51(12H,s), 4.0-4.3(2H,m), 7.29(5H,m)                                                                          189                         171      0.88(3H,t,J=7.4), 1.17(3H,d,J=6.8), 1.22(3H×2,t,J=7.2),                  1.3-2.0(8H,m), 2.4-2.8                    320(M.sup.+ +1)                                                                        0.38                         (10H,m), 3.0-3.4(1H,m), 4.1-4.3(2H,m)     111                         172      0.88(3H,t,J=7.3), 1.17(3H,d,J=6.3), 1.21(3H×2,t,J=7.2),                  1.4-2.0(2H,m), 2.3-2.8                    365(M.sup.+ +1)                                                                        0.09                         (6H,m), 3.1-3.3(1H,m), 3.61(2H,t,J=5.4), 4.0-4.3(2H,m)                                                                   156                         173      0.88(3H,t,J=7.5), 1.17(3H,d,J=6.8), 1.21(3H×2,t,J=7.1),                  1.2-1.9(2H,m), 2.4-2.8                    322(M.sup.+ +1)                                                                        0.42                         (10H,m), 3.1-3.4(1H,m), 3.6-4.0(4H,m), 4.0-4.3(2H,m)                                                                     103                         174      0.87(3H,t,J=7.2), 1.16(3H,d,J=6.8), 1.20(3H×2,t,J=6.6),                  1.3-1.9(2H,m), 2.4-2.8                    411(M.sup.+ +1)                                                                        0.43                         (14H,m), 3.0-3.4(1H,m), 3.53(2H,s), 4.1-4.3(2H,m), 7.30(5H,s)         175      0.87(3H,t,J=7.4), 1.1-1.3(9H,m), 1.3-2.0(2H,m), 2.4-2.7(14H,m),                3.0-3.4(1H,m),                            429(M.sup.+ +1)                                                                        0.42                         3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.3(2H,m)                                                                  220                         176      0.88(3H,t,J=7.6), 1.17(3H,d,J=7.1), 1.21(3H×2,t,J=7.1),                  1.4-2.0(2H,m), 2.3-2.8                    447(M.sup.+ +1)                                                                        0.42                         (14H,m), 3.0-3.4(1H,m), 3.47(2H,s), 4.0-4.3(2H,m),                                                                       4456(4H,s)                                                                     223                         177      0.87(3H,t,J=7.2), 1.17(3H,d,J=6.8), 1.21(3H×2,t,J=6.9),                  1.2-2.0(2H,m), 2.3-2.8                    447(M.sup.+ +1)                                                                        0.39                         (14H,m), 3.1-3.4(1H,m), 3.48(2H,s), 4.0-4.3(2H,m),                                                                       445-7.4(4H,m)                                                                  223                         178      0.93(3H,t,J= 6.4), 1.20(3H×2,t,J=7.4), 1.2-1.9(4H,m),                    2.2-2.9(16H,m), 3.63(2H,                  447(M.sup.+ +1)                                                                        0.43                         s), 3.9-4.3(2H,m), 7.1-7.5(4H,m)          445                                                                            223                         179      0.93(3H,t,J=6.4), 1.20(3H×2,t,J=7.5), 1.2-1.9(4H,m),                     2.2-2.8(16H,m), 3.52(2H,                  411(M.sup.+ +1)                                                                        0.46                         s), 3.9-4.3(2H,m), 7.29(5H,s)             189                         180      0.93(3H,t,J=6.4), 1.21(3H×2,t,J=7.4), 1.2-1.9(4H,m),                     2.2-2.9(16H,m), 3.47(2H,                  447(M.sup.+ +1)                                                                        0.43                         s), 3.9-4.3(2H,m), 7.26(4H,s)             445                                                                            223                         181      0.94(3H,t,J=6.6), 1.20(3H,t,J=7.6), 1.23(3H,t,J=7.6),                          1.2-1.9(10H,m), 2.4-2.9                   320(M.sup.+ +1)                                                                        0.40                         (12H,m), 4.1-4.4(2H,m)                                                182      0.94(3H,t,J=6.6), 1.21(3H,t,J=7.6), 1.23(3H,t,J=7.6),                          1.2-1.9(4H,m), 2.4-2.9(                   322(M.sup.+ +1)                                                                        0.39                         12H,m), 3.6-4.0(4H,m), 3.9-4.3(2H,m)      113                         183      0.93(3H,t,J=6.6), 1.20(3H×2,t,J=7.5), 1.2-1.8(4H,m),                     2.3-2.9(16H,m), 3.47(2H,                  429(M.sup.+ +1)                                                                        0.42                         s), 3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m)                                                                          207                         185      0.94(3H,t,J=6.4), 1.21(3H×2,t,J=7.4), 1.2-1.8(4H,m),                     2.2-2.9(16H,m), 3.48(2H,                  447(M.sup.+ +1)                      s), 4.0-4.3(2H,m)                         445                                                                            223                         187      1.22(3H×2,t,J=7.3), 1.23(3H,t,J=7.3), 2.4-2.9(12H,m),                    3.6-3.8(4H,m), 3.8-4.3(                   294(M.sup.+ +1)                                                                        0.39                         2H,m)                                     207                         188      1.21(3H×2,t,J=7.3), 1.22(3H,t,J=7.3), 2.3-2.9(16H,m),                    3.48(2H,s), 3.8- 4.3(2H,                  419(M.sup.+ +1)                                                                        0.40                         m), 7.26(4H,s)                            417                                                                            225                         189      1.21(3H×2,t,J=7.3), 1.22(3H,t,J=7.3), 2.4-2.9(16H,m),                    3.54(2H,s), 3.8-4.3(2H,                   383(M.sup.+ +1)                                                                        0.40                         m), 7.29(5H,s)                            189                         190      1.23(3H,t,J=7.5), 2.32(3H×2,s), 2.2-2.7(6H,m),                           2.78(2H,q,J=7.5), 3.6-3.8(4H,m),          266(M.sup.+ +1)                                                                        0.56                         4.16(2H,t,J=7.2)                          179                                                                            174                         191      1.22(3H,t,J=7.5), 2.31(3H×2,s), 2.3-2.7(10H,m),                          2.78(2H,q,J=7.5), 3.46(2H,s),             391(M.sup.+ +1)                                                                        0.49                         3.9-4.3(2H,m), 7.26(4H,s)                 389                         192      1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m),                      2.78(2H,q,J=7.5),                         373(M.sup.+ +1)                                                                        0.42                         3.47(2H,s), 3.9-4.3(2H,m), 6.8-7.3(4H,m)  207                                                                            179                         193      1.22(3H,t,J=7.5), 2.31(3H,s), 2.33(3H,s), 2.3-2.7(10H,m),                      2.78(2H,q,J=7.5),                         385(M.sup.+ +1)                                                                        0.50                         3.45(2H,s), 3.79(3H,s), 3.8-4.2(2H,m), 6.7-6.9(2H,m),                          7.1-7.3(2H,m)                             219                         250      0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.8-4.2(2H,m),                459(M.sup.+ +1)                                                                        0.36                         7.26(4H,s)                                457                                                                            247                                                                            223                         251      0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.48(2H,s), 3.8-4.2(2H,s),                441(M.sup.+ +1)                                                                        0.35                         6.8-7.3(4H,m)                             247                                                                            207                         252      0.89(3H,t,J=6.5), 1.1-1.5(4H,m), 1.5-1.9(6H,m), 2.4-2.8(12H,m),                3.5-3.7(4H,m),                            334(M.sup.+ +1)                                                                        0.35                         3.8-4.2(2H,m)                             114                         253      0.8-1.0(6H,m), 1.1-1.9(14H,m), 2.2-2.8(18H,m),                                                                           389(M.sup.+ +1)                                                                        0.29                                                                   155                                                                            125                         254      0.89(3H,t,J≈6.5), 1.1-1.9(10H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.80(3H,s), 3.8-              453(M.sup.+ +1)                                                                        0.34                         4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                            247                                                                            219                                                                            111                         255      0.88(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.4-2.9(12H,m),                      3.6-3.8(4H,m), 3.9-4.2(2H,m)              348(M.sup.+ +1)                                                                        0.51                                                                   113                         256      0.87(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m),                      3.47(2H,s), 3.9-4.2(2H,m),                473 471 0.49                         7.26(4H,s)                                (M.sup.+ +1)                                                                   238                                                                            236                                                                            112                         257      0.87(3H,t,J≈6.3), 1.1-1.9(12H,m), 2.3-2.8(16H,m),                      3.59(2H,s), 3.9-4.2(2H,m),                482(M.sup.+ +1)                                                                        0.42                         7.50(2H,d,J=8.8), 8.16(2H,d,J=8.8)        347                                                                            234                                                                            112                         258      0.87(3H,t,J≈6), 1.2-2.0(14H,m), 2.5-2.9(16H,m),                        3.60(2H,s), 3.9-4.2(2H,s),                469(M.sup.+ +1)                                                                        0.46                         6.8-7.4(4H,m)                             235                                                                            221                         259      0.87(3H,t,J=6.5), 1.1-1.9(14H,m), 2.4-2.9(12H,m), 3.4-3.8(4H,m),               3.9-4.2(2H,m)                             362(M.sup.+ +1)                                                                        0.41                                                                   114                         260      0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),                485,487 0.40                         7.26(4H,s)                                (M.sup.+ +1)                                                                   223                         261      0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.4-2.8(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),                496(M.sup.+ +1)                                                                        0.46                         7.49(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                               234                         262      0.87(3H,t,J≈6), 1.1-1.9(14H,m), 2.3-2.9(16H,m),                        3.49(2H,s), 3.9-4.1(2H,m),                469(M.sup.+ +1)                                                                        0.42                         6.8-7.3(4H,m)                             275                                                                            207                         263      0.8-1.0(6H,m), 1.1-1.6(12H,m), 1.5-1.9(6H,m), 2.1-2.9(18H,m),                  3.9-4.2(2H,m)                             417(M.sup.+ +1)                                                                        0.43                                                                   155                         264      0.87(3H,t,J=6), 1.1-2.0(16H,m), 2.5-2.9(16H,m), 3.59(2H,s),                    3.9-4.2(2H,m),                            498 500 0.45                         7.27(4H,s)                                (M.sup.+ +1)                                                                   250                                                                            237                         265      0.87(3H,t,J≈6), 1.1-1.9(16H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)              376(M.sup.+ +)                                                                         0.47                                                                   114                         266      0.87(3H,t,J≈6), 1.1-1.9(16H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),                499 501 0.43                         7.26(4H,s)                                (M.sup.+ +1)                                                                   289                                                                            223                         267      0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.80(3H,s), 3.9-              495(M.sup.+ +1)                                                                        0.42                         4.1(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                            232                         268      0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.59(2H,s), 3.8-4.2(2H,m), 7.5            510(M.sup.+ +1)                                                                        0.46                         (2H,d,J=8.8), 8.17(2H,d,J=8.8)            234                         269      0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m), 6.8            483(M.sup.+ +1)                                                                        0.51                         -7.3(4H,m)                                289                                                                            207                         270      0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.9-4.1(2H,m), 6.8            497(M.sup.+ +1)                                                                        0.45                         -7.3(4H,m)                                235                                                                            221                         271      0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)              390(M.sup.+ +1)                                                                        0.48                272      0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m),                513 515 0.51                         7.26(4H,s)                                (M.sup.+ +1)                                                                   223                         273      0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.4-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m), 6.8            497(M.sup.+ +1)                                                                        0.48                         -7.3(4H,m)                                207                         274      0.87(3H,t,J≈6), 1.1-1.9(18H,m), 2.3-2.9(16H,m),                        3.59(2H,s), 3.9-4.3(2H,m),                524(M.sup.+ +1)                                                                        0.52                         7.50(2H,d,J=8.8), 8.17(2H,d,J=8.8)        247                                                                            234                         275      0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.80(3H,s), 3.9-              509(M.sup.+ +1)                                                                        0.43                         4.2(2H,m), 6.85(2H,d,J=8.8), 7.23(2H,d,J=8.8)                                                                            232                                                                            219                         276      0.87(3H,t,J≈6), 1.1-1.9(24H,m), 2.4-2.9(12H,m),                        3.6-3.8(4H,m), 3.9-4.2(2H,m)              432(M.sup.+ +1)                                                                        0.45                277      0.87(3H,t,J≈6), 1.1-2.0(24H,m), 2.3-2.9(16H,m),                        3.47(2H,s), 3.9-4.2(2H,m),                555 557 0.44                         7.26(4H,s)                                (M.sup.+ +1)                                                                   345                                                                            236                                                                            223                         278      0.87(3H,t,J≈6), 1.1-2.0(26H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.9-4.1(2H,m), 6.8            553(M.sup.+ +1)                                                                        0.46                         -7.3(4H,m)                                235                                                                            221                         279      0.87(3H,t,J≈6), 1.1-2.0(24H,m), 2.3-2.9(16H,m),                        3.58(3H,s), 3.9-4.3(2H,m),                566(M.sup.+ +1)                                                                        0.47                         7.49(2H,d,J=8.6), 8.17(2H,d,J=8.6)        431                                                                            247                                                                            112                         280      0.88(3H,t,J≈6), 1.1-1.9(28H,m), 2.4-2.9(12H,m),                        3.5-3.7(4H,m), 3.9-4.2(2H,m)              460(M.sup.+ +1)                                                                        0.53                                                                   114                         281      0.88(3H,t,J≈6), 1.1-2.0(28H,m), 2.3-2.9(16H,m),                        3.45(2H,s), 3.79(3H,s), 3.9-              579(M.sup.+ +1)                                                                        0.44                         4.2(2H,m), 6.84(2H,d,J=8.7), 7.22(2H,d,J=8.7)                                                                            232                                                                            219                         282      0.88(3H,t,J≈6), 1.1-2.0(30H,m), 2.5-2.9(16H,m),                        3.59(3H,s), 3.9-4.1(2H,m), 6.8            581(M.sup.+ +1)                                                                        0.50                         -7.3(4H,m)                                234                                                                            221                         283      0.88(3H,t,J≈6), 1.1-1.7(32H,m), 2.4-2.9(12H,m),                        3.5-3.7(4H,m), 3.9-4.2(2H,m)              488(M.sup.+ +1)                                                                        0.54                                                                   114                         284      0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.3-2.9(16H,m),                        3.46(2H,s), 3.9-4.2(2H,m),                611 613 0.50                         7.26(4H,s)                                (M.sup.+ +1)                                                                   279                                                                            236                         285      0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.3-2.9(16H,m),                        3.58(2H,s), 3.9-4.2(2H,m),                622(M.sup.+ +1)                                                                        0.50                         7.49(2H,d,J=8.8), 8.19(2H,d,J=8.8)        419                                                                            208                         286      0.88(3H,t,J≈6), 1.1-2.0(34H,m), 2.5-2.9(16H,m),                        3.59(2H,s), 3.8-4.1(2H,m),                627 625 0.48                         7.26(4H,s)                                (M.sup.+ +1)                                                                   307                                                                            250                         287      1.23(3H,t,J=7.5), 2.31(3H×2,s), 2.3-3.0(12H,m),                          3.51(2H,s), 3.9-4.3(2H,m),                355(M.sup.+ +1)                                                                        0.49                         7.29(5H,s)                                179                         288      1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3H×2,s),                           2.4-3.0(12H,m), 3.59(2H,s), 3.9           391(M.sup.+ +1)                                                                        0.40                         -4.2(2H,m), 7.27(4H,s)                    389                         289      1.23(3H,t,J=7.5), 1.6-1.9(2H,m), 2.31(3H×2,s),                           2.4-3.0(12H,m), 3.60(2H,s),               387(M.sup.+ +1)                                                                        0.39                         3.9-4.2(2H,m), 6.8-7.4(4H,m)              225                                                                            221                                                                            179                         290      1.23(3H,t,J=7.5), 2.31(3H×2,s), 2.3-3.0(12H,m),                          3.59(2H,s), 3.9-4.3(2H,m),                400(M.sup.+ +1)                                                                        0.44                         7.50(2H,d,J=8.7), 8.17(2H,d,J=8.7)        234                                                                            179                         291      1.21(3H×2,t,J=7.6), 2.4-2.8(10H,m), 3.5-3.7(2H,m),                       3.8-4.2(4H,m), 4.09(2H,s),                356     0.36                         7.0-7.4(5H,m)                                                         292      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 1.3-1.8(6H,m),                             2.3-2.8(10H,m), 3.8-4.3(2H,               354     0.40                         m), 4.09(2H,s), 7.0-7.5(5H,m)                                         293      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.50(2H,s),                3.8-4.2(2H,m),                            444     0.36                         4.08(2H,s), 7.0-7.4(10H,m)                202                                                                            189                         294      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.45(2H,s),                3.8-4.2(2H,m),                            479,                                                                                   0.36                         4.08(2H,s), 7.0-7.4(9H,m)                 236                         295      1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.3-2.8(14H,m), 3.56(2H,s),                4.09(2H,s)                                513,515 0.60                         3.8-4.2(2H,m), 7.0-7.4(8H,m)              517                                                                            237                                                                            219                         296      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2-2.8(14H,m), 3.45(2H,s),                3.8-4.2(2H,m),                            462     0.37                         4.08(2H,s), 6.8-7.4(9H,m)                 207                         297      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.2-2.7(14H,m), 3.43(2H,s),                3.79(3H,s),                               474     0.37                         3.8-4.2(2H,m), 4.08(2H,s), 6.83(2H,d,J=8.8), 7.0-7.4(7H,m)                                                               232                                                                            219                         305      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.4-2.9(12H,m),                      3.0-3.4(6H,m), 4.0-4.3(2H,                423,422 0.65                         m), 7.1-7.3(5H,m)                         174                         306      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.51(2H,s), 3.9-4.2(2H,m),                437     0.36                         7.29(5H,s)                                189                         307      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.46(2H,s), 3.9-4.2(2H,m),                455     0.38                         6.8-7.4(14H,m)                            207                         308      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.3-2.9(16H,m),                      3.45(2H,s), 3.79(3H,s), 3.9-              467     0.40                         4.2(2H,m), 6.84(2H,d,J=8.6), 7.22(2H,d,J=8.6)                                                                            219                         309      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m),                      3.0-3.2(4H,m), 4.0-4.3(2H,                457,459 0.36                         m), 6.8-7.4(4H,m)                         209                         310      0.87(3H,t,J≈5.7), 1.2-2.0(12H,m), 2.6-2.9(12H,m),                      3.0-3.2(4H,m), 3.89(3H,s),                453     0.53                         4.0-4.3(2H,m), 7.7-8.1(4H,m)              203                         311      0.87(3H,t,J≈5.6), 1.2-2.0(14H,m), 2.6-3.0(16H,m),                      3.72(2H,s), 3.9-4.2(2H,m),                496     0.43                         7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)        301                                                                            248                         312      0.87(3H,t,J≈5.6), 1.2-2.0(14H,m), 2.5-3.0(16H,m),                      3.59(2H,s), 3.9-4.2(2H,m),                485,487 0.49                         7.28(4H,s)                                237                         313      0.87(3H,t,J≈5.7), 1.2-2.0(14H,m), 2.6-2.9(16H,m),                      3.58(2H,s), 3.80(3H,s), 3.9-              481     0.48                         4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                                            247                                                                            233                         314      0.87(3H,t,J≈5.7), 1.1- 1.9(14H,m), 2.3-2.9(16H,m),                     3.51(2H,s), 3.9-4.1(2H,m),                451     0.48                         7.30(5H,s)                                189                         315      0.87(3H,t,J≈5.6), 1.1-1.9(14H,m), 2.5-2.9(12H,m),                      3.1-3.3(4H,m), 4.0-4.2(2H,m),             437     0.60                         6.7-8.3(5H,m)                             189                                                                            175                         316      0.87(3H,t,J≈5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m),                      2.9-3.2(4H,m), 3.86(3H,s),                467     0.65                         3.9-4.2(2H,m), 6.7-7.1(4H,m)              203                         317      0.87(3H,t,J≈5.6), 1.1-2.0(14H,m), 2.5-2.9(12H,m),                      2.9-3.2(4H,m), 4.0-4.2(2H,                471,473 0.72                         m), 6.7-7.4(4H,m)                         209                         318      0.87(3H,t,J≈5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m),                      3.59(2H,s), 3.9-4.1(2H,m),                483     0.40                         6.8-7.3(4H,m)                             221                         319      0.87(3H,t,J≈5.6), 1.2-2.0(16H,m), 2.5-3.0(16H,m),                      3.58(2H,s), 3.8(3H,s), 3.9-               495     0.44                         4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                                            246,247                     320      0.87(3H,t,J≈5.6), 1.1-2.0(16H,m), 2.5-2.9(16H,m),                      3.72(2H,s), 3.9-4.1(2H,m),                510     0.45                         7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)                                    321      0.87(3H,t,J≈5.6), 1.0-2.0(16H,m), 2.3-2.8(16H,m),                      3.51(2H,s), 3.9-4.2(2H,m),                465     0.50                         7.29(5H,s)                                189                         322      0.87(3H,t,J≈6), 1.0-2.0(16H,m), 2.5-2.9(12H,m),                        3.0-3.3(4H,m), 4.0-4.2(2H,m),             451     0.55                         6.7-7.4(5H,m)                             175                         323      0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.5-2.9(12H,m),                        2.9-3.2(4H,m), 3.58(3H,s),                481     0.57                         4.0-4.2(2H,m), 6.7-7.1(4H,m)              205                         324      0.87(3H,t,J≈6), 1.0-2.0(16H,m), 2.5-2.9(12H,m),                        2.9-3.2(4H,m), 4.0-4.2(2H,m),             485,487 0.52                         6.8-7.4(4H,m)                             209                         325      0.87(3H,t,J≈5.6), 1.1-2.0(18H,m), 2.5-3.0(16H,m),                      3.72(2H,s), 3.9-4.2(2H,m),                523     0.41                         7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                               339                                                                            248                         326      0.87(3H,t,J≈6), 1.1-2.2(18H,m), 2.5-3.0(16H,m),                        3.58(2H,s), 3.80(3H,s), 3.9-              509     0.41                         4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                                            247                                                                            233                         327      0.87(3H,t,J≈6), 1.1-2.2(18H,m), 2.5-3.0(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),                513,515 0.43                         7.26(4H,s)                                237                         328      0.87(3H,t,J≈6), 1.2-2.2(18H,m), 2.4-2.9(16H,m),                        3.51(2H,s), 3.9-4.2(2H,m),                479     0.48                         7.29(5H,s)                                189                         329      0.87(3H,t,J≈6), 1.1-2.1(20H,m), 2.4-3.0(16H,m),                        3.59(2H,s), 3.9-4.2(2H,m),                527,529 0.49                         7.26(4H,s)                                237                         330      0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.72(2H,s), 3.9-4.2(2H,m),                538     0.51                         7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                               402                         331      0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.60(2H,s), 3.9-4.2(2H,m),                511     0.45                         6.8-7.4(4H,m)                             220                         332      0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.5-3.0(16H,m),                        3.58(2H,s), 3.80(3H,s), 3.9-              523     0.43                         4.2(2H,m), 6.84(2H,d,J=8.4), 7.24(2H,d,J=8.4)                                                                            247                                                                            233                         334      0.87(3H,t,J≈6), 1.1-2.0(20H,m), 2.3-2.9(12H,m),                        3.5-3.8(4H,m), 3.9-4.2(2H,m)              404     0.46                                                                   102                         335      0.87(3H,t,J≈6), 1.1-2.2(20H,m), 2.3-2.9(16H,m),                        3.51(2H,s), 3.9-4.2(2H,m),                493     0.47                         7.29(5H,s)                                189                         336      0.87(3H,t,J≈6), 1.0-2.0(10H,m), 2.5-2.9(12H,m),                        3.0-3.3(4H,m), 3.9-4.2(2H,m),             479     0.54                         6.7-7.4(4H,m)                             190                                                                            175                         337      0.87(3H,t,J≈6), 1.0-2.0(20H,m), 2.1-2.9(16H,m),                        3.45(2H,s), 3.79(3H,s), 3.9-              523     0.47                         4.2(2H,m), 6.84(2H,d,J= 8.8), 7.12(2H,d,J=8.8)                                                                           232                                                                            219                         338      0.87(3H,t,J≈6), 1.0-2.2(20H,m), 2.3-2.9(16H,m),                        3.9-4.2(2H,m), 7.26(4H,s)                 527,529 0.48                                                                   235                                                                            223                         339      0.87(3H,t,J≈6), 1.0-2.0(22H,m), 2.5-3.0(16H,m),                        3.72(2H,s), 3.9-4.2(2H,m),                552     0.49                         7.51(2H,d,J=8.8), 8.17(2H,d,J=8.8)        417                                                                            248                         340      0.87(3H,t,J≈6), 1.1-2.1(22H,m), 2.5-3.0(16H,m),                        3.60(2H,s), 3.9-4.2(2H,m),                541,543 0.48                         7.27(4H,s)                                251                                                                            237                         374      1.21(3H×2,t,J=7.6), 1.7-2.0(4H,m), 2.1-3.3(11H,m),                       4.10(2H,s), 4.1-4.3(2H,m),                430     0.74                         7.1-7.5(10H,m)                            134                         375      0.91(3H,d,J=4.9), 1.19(3H,t,J=7.7), 1.20(3H,t,J=7.7),                          1.4-2.3(5H,m), 2.4-3.0                    368     0.53                         (10H,m), 3.9-4.2(2H,m), 4.09(2H,s), 7.1-7.5(5H,m)                                                                        112                         378      1.19(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.4-2.7(14H,m), 3.58(2H,s),                4.09(2H,s),                               490     0.49                         3.8-4.3(2H,m), 7.1-7.5(7H,m), 8.16(2H,d,J=8.8)                                                                           247                                                                            191                         380      1.21(3H×2,t,J=7.6), 2.4-3.6(14H,m), 4.10(2H,s),                          4.0-4.4(2H,m), 6.8-7.5(10H,m)             431     0.63                                                                   188,189                                                                        175                         384      1.20(3H×2,t,J≈7.4), 2.2-2.8(10H,m), 3.6-4.3(6H,m),               4.04(2H,s), 7.1-7.4(4H,m)                 392     0.43                                                                   390                                                                            114                         385      1.19(3H×2,tJ≈ 7.6), 2.2-2.8(14H,m), 3.46(2H,s),                  3.8-4.3(2H,m), 4.04(2H,s), 7.1            517     0.48                         -7.4(8H,m)                                515                                                                            513                                                                            303                                                                            223                         386      1.19(3H×2,t,J≈7.6), 2.1-2.8(14H,m), 3.46(2H,s),                  3.79(3H,s), 3.9-4.2(2H,m),                511     0.42                         4.03(2H,s), 6.84(2H,d,J≈8.8), 7.1-7.4(6H,m)                                                                      509                                                                            232                                                                            219                         387      1.19(3H,t,J=7.1), 1.20(3H,t,J=7.1), 2.3-2.8(14H,m), 3.47(2H,s),                4.05(2H,s),                               526     0.43                         4.1-4.3(2H,m), 7.52(2H,d,J=8.8), 7.26(4H,s), 8.17(2H,d,J=8.8)                                                            524                                                                            247                         454      1.23(3H,t,J≈7.4), 2.32(3H,s), 2.33(3H,s),                              2.4-3.0(13H,m), 4.0-4.2(2H,m)             265                                                                            179                         455      1.22(3H,t,J≈7.4), 2.30(3H×2,s), 2.2-3.0(8H,m),                   3.44(2H,t,J≈5), 3.65(2H,t,J≈5),                                                                          383                                  3.72(2H,s), 4.0-4.2(2H,m), 7.1-7.4(5H,m)  217                                                                            139                         456      1.22(3H,t,J=7.4), 2.32(3H×2,s), 2.4=2.9(8H,m),                           3.3-3.8(4H,m), 4.0-4.3(2H,m),             405                                  7.36(4H,s)                                403                                                                            251                                                                            237                         457      1.23(3H,t,J=7.4), 2.31(3H×2,s), 2.3-2.9(8H,m),                           3.51(2H,t,J≈5), 3.65(2H,t,J≈5),                                                                          389                                  3.90(2H,s), 4.0-4.2(2H,m), 6.8-7.3(3H,m)  223                         458      1.22(3H,t,J=7.4), 2.32(3H×2,s), 2.4-3.0(8H,m),                           3.2-3.5(2H,m), 3.5-3.9(2H,m),             414                                  4.0-4.3(2H,m), 7.56(2H,d,J=8.8), 8.28(2H,d,J=8.8)                                                                        262                                                                            248                         459      1.23(3H,t,J=7.4), 2.31(3H×2,s), 2.4-3.0(8H,m),                           3.48(2H,t,J≈5), 3.65(2H,t,J=5),   428                                  3.81(2H,s), 4.0-4.3(2H,m), 7.41(2H,d,J=8.6), 8.19(2H,d,J=8.6)                                                            265                         460      1.23(3H,t,J=7.4), 2.32(3H×2,s), 2.4-2.9(8H,m),                           3.5-3.7(4H,m), 3.83(3H,s), 4.0-           399                                  4.3(2H,m), 6.8-7.0(2H,m), 7.3-7.5(2H,m)   247                                                                            233                         461      1.22(3H,t,J=7.4), 2.31(3H×2,s), 2.2-3.0(8H,m),                           3.1-3.4(2H,m), 3.6-3.9(2H,m),             429                                  3.85(3H,s), 3.88(3H,s), 4.0-4.3(2H,m), 6.7-7.2(3H,m)                                                                     277                                                                            263                                                                            164                         462      1.22(3H,t,J=7.4), 2.31(3H×2,s), 2.2-3.0(8H,m),                           3.1-3.4(2H,m), 3.6-3.8(2H,m),             429                                  3.82(3H×2,s), 4.0-4.3(2H,m), 6.5-6.7(2H,m),                                                                        277-7.2(1H,m)                                                                  263                                                                            164                         463      1.23(3H,t,J=7.4), 2.32(3H×2,s), 2.4-3.0(8H,m),                           3.7-3.9(4H,m), 3.90(3H,s), 3191           429                                  (3H,s), 4.0-4.3(2H,m), 6.7-7.0(3H,m)      277                                                                            263                                                                            164                         464      1.22(3H,t,J=7.4), 2.32(3H×2,s), 2.4-3.0(8H,m),                           3.4-3.8(4H,m), 3.87(3H×2,s),        459                                  4.0-4.3(2H,m), 6.61(2H,s)                 306                                                                            195                         465      1.17(3H,t,J≈7.4), 2.37(3H×2,s), 2.4-2.9(8H,m),                   2.9-3.1(4H,m), 3.9-4.2(2H,m),             441                                  7.4-7.8(4H,m)                             439                                                                            287                                                                            283                         467      1.18(3H×2,t,J≈7.4), 2.3-2.8(14H,m), 3.51(2H,s),                  3.9-4.2(2H,m), 4.03(2H,s), 7.1            481(M.sup.+ +1)                      -7.4(9H,m)                                479                         468      1.19(3H,t,J≈7.4), 1.20(3H,t,J≈7.4),                            2.3-2.8(14H,m), 3.58(2H,s), 3.8-4.0(2H,m),                                                                               526(M.sup.+ +1)                      4.05(2H,s), 4.1-4.3(2H,m), 7.0-7.5(2H,m), 7.26(4H,s),                          8.17(2H,d,J=8.8)                          524                                                                            247                         470      1.6-2.0(4H,m), 2.4-2.8(10H,m), 3.5-3.8(4H,m), 3.9-4.2(2H,m),                   4.09(2H,s), 7.0-                          354(M.sup.+ +1)                      7.5(5H,m)                                 114                         471      1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.50(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 7.1-7.5                       443(M.sup.+ +1)                      (10H,m)                                   189                         472      1.6-2.0(4H,m), 2.5-2.9(1oH,m), 3.0-3.3(4H,m), 3.9-4.2(2H,m),                   4.10(2H,s), 6.7-                          429(M.sup. + +1)                     7.5(10H,m)                                175                         473      1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.45(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 7.1-7.5                       479(M.sup.+ +1)                      (5H,m), 7.25(4H,s)                        477                                                                            223                         474      1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.44(2H,s), 3.79(3H,s),                         3.9-4.1(2H,m), 4.09(                      473(M.sup.+ +1)                      2H,s), 6.84(2H,d,J≈8.8), 7.0-7.5(7H,m)                                                                           219                         475      1.6-2.0(4H,m), 2.3-2.8(14H,m), 3.46(2H,s), 3.9-4.1(2H,m),                      4.09(2H,s), 6.8-7.5                       461(M.sup.+ +1)                      (9H,m)                                    207                         476      1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 4.6-4.8(4H,m),                   3.9-4.2(2H,m),                            368(M.sup.+ +1)                      7.1-7.4(5H,m)                             114                         477      1.6-1.9(4H,m), 2.4-2.8(14H,m), 2.9-3.2(4H,m), 3.52(2H,s),                      3.9-4.2(2H,m), 7.1-                       457(M.sup.+ +1)                      7.4(10H,m)                                189                         478      1.6-2.0(4H,m), 2.4-2.9(10H,m), 2.9-3.4(8H,m), 4.0-4.2(2H,m),                   6.7-7.4(10H,m)                            443(M.sup.+ +1)                                                                175                         479      1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.47(2H,s),                      3.9-4.2(2H,m), 7.0-                       493(M.sup.+ +1)                      7.4(5H,m), 7.26(4H,s)                     491                                                                            236                                                                            223                         480      1.6-2.0(4H,m), 2.3-2.8(14H,m), 2.9-3.2(4H,m), 3.45(2H,s),                      3.79(3H,s), 3.9-4.2                       407(M.sup.+ +1)                      (2H,m), 6.92(2H,d,J≈8.8), 7.0-7.4(7H,m)                                                                          232                                                                            219                         481      1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(12H,m), 3.5-3.8(4H,m),                3.9-4.2(2H,m)                             292(M.sup.+ +1)             482      1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s),                   3.9-4.2(2H,m),                            417(M.sup.+ +1)                      7.27(4H,s)                                415                                                                            223                         483      1.23(3H,t,J=7.4), 1.6-2.0(4H,m), 2.4-3.0(16H,m), 3.52(2H,s),                   3.9-4.2(2H,m),                            381(M.sup.+ +1)                      7.2-7.3(5H,m)                             189                         484      1.24(3H,t,J=7.4), 1.6-2.0(4H,m), 2.6-3.0(12H,m), 3.1-3.3(4H,m),                4.0-4.3(2H,m),                            367(M.sup.+ +1)                      6.7-7.4(5H,m)                             175                         485      1.23(3H,t,J=7.4), 1.6-2.0(6H,m), 2.4-3.0(16H,m), 3.59(2H,s),                   3.9-4.2(2H,m),                            431(M.sup.+ +1)                      7.27(4H,s)                                429                                                                            237                         486      1.22(3H,t,J=7.4), 1.6-2.0(4H,m), 2.3-3.0(16H,m), 3.47(2H,s),                   3.80(3H,s), 3.9-                          411(M.sup.+ +1)                      4.2(2H,m), 6.84(2H,d,J=8.8), 7.23(2H,d,J=8.8)                                                                            219                         487      0.88(3H,t,J≈6), 1.1-1.5(20H,m), 1.5-2.0(10H,m),                        2.4-2.9(14H,m), 3.51(2H,s),               549(M.sup.+ +1)                      3.9-4.2(2H,m), 7.29(5H,s)                 202                                                                            121                         488      0.88(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.5-3.0(14H,m), 3.72(2H,s),               608(M.sup.+ +1)                      3.9-4.2(2H,m), 7.51(2H,d,J≈8.8), 8.17(2H,d,J=8.8)                                                                473                         489      0.88(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.4-2.9(14H,m), 3.54(2H,s),               599                                  3.9-4.2(2H,m), 7.27(4H,s)                 597                         490      0.87(3H,t,J≈6), 1.1-1.5(22H,m), 1.5-2.0(10H,m),                        2.5-3.0(14H,m), 3.59(2H,s),               593(M.sup.+ +1)                      3.80(3H,s), 3.9-4.2(2H,m), 6.84(2H,d,J=8.8), 7.24(2H,d,J=8.8)                                                            246                                                                            101                         611      2.30(3H,s), 2.34(3H,s), 2.4(3H,s), 2.5-3.0(9H,m),                                                                        250(M.sup.+ +1)                                                                        0.04                612      2.44(3H×2,s), 3.91(2H,t,J≈6.3), 4.43(2H,t,J.apprxeq              .6.3), 8.1-8.3(5H,m)                      265 263 0.79                                                                   (M.sup.+ +1)                613      2.33(3H×2,s), 3.80(2H,t,J=5.4), 4.09(2H,s),                              4.29(2H,t,J=5.4), 7.1-7.5(5H,m)           278 276                                                                        (M.sup.+ +1)                614      0.99(3H,t,J=7.3), 1.5-1.9(6H,m), 2.5-2.9(6H,m), 3.38(1H,bs),                   3.8-4.0(2H,m),                            237(M.sup.+ +1)                                                                        0.34                         4.1-4.3(2H,m)                             164                         615      0.99(3H,t,J=7.3), 1.5-2.0(6H,m), 2.3-2.8(6H,m), 3.1-3.4(2H,m),                 4.0-4.2(2H,m),                            329(M.sup.+ +1)                      7.1-7.6(5H,m)                             319                         616      0.99(3H,t,J=7.2), 1.5-2.0(2H,m), 2.33(3H×2,s),                           2.74(2H,t,J=7.7), 3.8-4.0(2H,             211(M.sup.+ +1)                                                                        0.29                         m), 4.1-4.3(2H,m)                                                     617      0.94(3H×2,d,J=6.6), 1.8-2.4(1H,m), 2.33(3H×3,s),                   2.64(2H,d,J=7.1), 3.8-4.0(2H,             225(M.sup.+ +1)                                                                        0.29                         m), 4.1-4.3(2H,m)                                                     618      0.95(3H×2,d,J=6.6), 1.6-2.0(4H,m), 2.0-2.4(1H,m),                        2.5-2.8(6H,m), 3.8-4.0(2H,                251(M.sup.+ +1)                                                                        0.34                         m), 4.1-4.3(2H,m)                                                     619      0.93(3H×2,d,J=6.4), 2.0-2.4(1H,m), 2.31(2H×2,s),                   2.3-2.7(12H,m), 3.46(2H,s),               401(M.sup.+ +1)                                                                        0.34                         3.9-4.3(2H,m), 6.8-7.1(2H,m), 7.1-7.4(2H,m)                                                                              207                         620      1.00(3H,t,J=7.3), 1.21(3H×2,t,J=7.5), 1.5-1.9(2H,m),                     2.4-2.9(6H,m), 3.9-4.0(                   239(M.sup.+ +1)                                                                        0.44                         2H,m), 4.1-4.3(2H,m)                                                  621      0.94(3H,t,J=7.0), 1.2- 2.0(8H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                4.0-4.3(2H,m)                             251(M.sup.+ +1)                                                                        0.32                622      1.20(3H×2,d,J=6.8), 2.32(3H×2,s), 3.41(1H,                         sept,J=6.8), 3.8-4.1(2H,m), 4.1-4.3(      211(M.sup.+ +1)                                                                        0.36                         m)                                                                    623      0.79(3H,t,J=7.3), 1.18*3H,d,J=6.9), 1.3-2.0(3H,t,J=7.4),                       1.11(3H,d,J=6.9), 1.3                     225(M.sup.+ +1)                                                                        0.35                         -2.0(2H,m), 2.32(3H×2,s), 3.22(1H,sept,J=6.9),                           3.94(2H,t,J=5.2), 4.26(2H,t,J=                                                 5.2)                                                                  624      0.93(3H,t,J=6.7), 1.2-2.0(4H,m), 2.33(3H×2,s),                           2.77(2H,t,J=5.6), 3.7-4.0(2H,             225(M.sup.+ +1)                                                                        0.33                         m), 4.1-4.3(2H,m)                                                     625      1.1-1.4(12H,m), 2.55(2H,t,J=7.6), 2.72(2H,t,J=7.6),                            3.41(1H,sept,J=6.9), 3.72                 239(M.sup.+ +1)                                                                        0.40                         (1H,bs), 3.8-4.1(2H,m), 4.26(2H,t,J=5.1)  195                         626      0.95(3H×2,d,J=6.4), 1.21(3H×2,t,J=7.4),                            2.0-2.4(1H,m), 2.4-2.9(6H,m), 3.8-4.0(    253(M.sup.+ +1)                                                                        0.34                         2H,m), 4.1-4.3(2H,m)                      210                         627      0.88(3H,t,J=7.5), 1.0-1.4(9H,m), 1.2-2.2(2H,m), 2.4-2.8(4H,m),                 3.1-3.4(1H,m),                            253(M.sup.+ +1)                                                                        0.34                         3.8-4.0(2H,m), 4.1-4.3(2H,m)                                          628      0.97(3H×2,d,J=6.4), 1.21(3H×2,t,J=7.4),                            1.2-1.9(4H,m), 2.4-2.9(6H,m), 3.8-4.0(    253(M.sup.+ +1)                                                                        0.37                         2H,m)                                     210                         629      1.1-1.4(9H,m), 2.4-2.6(6H,m), 3.93(3H,t,J=5.1),                                                                          225(M.sup.+ +1))                                                                       0.33                                                                   130                         630      1.21(3H,t,J=7.5), 2.32(3H×2,s), 2.77(2H,q,J= 7.5),                       3.92(2H,t,J=5.0), 4.24(2H,t,              197(M.sup.+ +1)                      J=5.0)                                    153                         631      0.89(3H,t,J=6.6), 1.2=1.9(10H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                4.0-4.3(3H,m)                             265(M.sup.+ +1)                                                                        0.32                                                                   239                                                                            208                         632      0.88(3H,t,J=6.6), 1.2-1.9(12H,m), 2.5-2.9(6H,m), 3.8-4.0(2H,m),                4.0-4.3(2H,m)                             265(M.sup.+ +1)                                                                        0.33                                                                   219                                                                            208                         633      0.87(3H,t,J≈6), 1.1-2.0(14H,m), 2.5-2.9(6H,m),                         3.8-4.0(2H,m), 4.0-4.3(2H,m)              293(M.sup.+ +1)                                                                        0.34                                                                   247                                                                            208                         634      0.87(3H,t,J≈6), 1.1-2.0(16H,m), 2.5-2.9(6H,m),                         3.8-4.0(2H,m), 4.0-4.3(2H,m)              307(M.sup.+ +1)                                                                        0.38                                                                   208                         635      0.87(3H,t,J≈6), 1.1-2.0(18H,m), 2.5-2.9(6H,m),                         3.3(1H,bs), 3.8-4.0(2H,m), 4.0-           321(M.sup.+ +1)                                                                        0.39                         4.3(2H,m)                                                             636      0.87(3H,t,J≈6), 1.2-2.0(20H,m), 2.5-2.9(6H,m),                         3.3(1H,bs), 3.8-4.0(2H,m), 4.1-           335(M.sup.+ +1)                                                                        0.35                         4.3(2H,m)                                 208                         637      0.88(3H,t,J≈6), 1.1-2.0(24H,m), 2.5-2.9(6H,m),                         3.34(1H,bs), 3.8-4.0(2H,m),               363(M.sup.+ +1)                                                                        0.41                         4.0-4.3(2H,m)                                                         638      0.88(3H,t,J≈6), 1.1-2.0(28H,m), 2.5-2.9(6H,m),                         3.20(1H,bs), 3.8-4.0(2H,m),               391(M.sup.+ +1)                                                                        0.41                         4.0-4.3(2H,m)                                                         639      0.88(3H,t,J≈6), 1.1-2.0(32H,m), 2.5-2.9(6H,m),                         3.25(1H,bs), 3.8-4.0(2H,m),               419(M.sup.+ +1)                                                                        0.46                         4.0-4.3(2H,m)                                                         640      1.18(3H,t,J=7.6), 1.20(3H,t,J=7.6), 2.58(2H,q,J=7.6),                          2.68(2H,q,J=7.6), 3.89(                   286(M.sup.+ +1)                                                                        0.31                         2H,t,J≈6.6), 4.08(2H,s), 4.19(2H,t,J≈6),                       7.0-7.4(5H,m)                                                         641      1.19(3H,t,J≈7.7), 1.20(3H,t,J=7.7), 2.58(2H,q,J=7.7),                  2.69(2H,q,J=7.7), 3.8-                    323     0.26                         4.0(2H,m), 4.05(2H,s), 4.21(2H,t,J=5.2), 7.1-7.4(4H,m)                                                                   321                         642      2.30(3H,m), 2.34(3H,s), 2.41(3H,s), 2.5-3.0(8H,m),                                                                       250(M.sup.+ +1)                                                                        0.06                643      1.6-1.9(4H,m), 2.5-2.8(4H,m), 3.7-4.0(2H,m), 4.09(2H,s),                       4.0-4.2(2H,m), 7.0-                       255(M.sup.+ +1)                      7.4(5H,m)                                                             644      1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.79(2H,t,J≈7),                          4.10(2H,s), 4.23(2H,t,J≈7), 7.0-  305                                  7.5(5H,m)                                 303                                                                            267                                                                            239                         645      1.6-2.0(4H,m), 2.5-2.8(4H,m), 3.03(2H×2,s),                              3.90(2H,t,J≈5), 4.18(2H,t,J≈5),                                                                          299                                  7.0-7.4(5H,m)                                                         646      1.22(3H,t,J≈7.3), 1.7-4.0(4H,m), 2.6-3.8(4H,m),                        3.78(2H,q,J≈7.3), 3.7-4.0(2H,     223                                  m), 4.0-4.3(2H,m)                                                     647      1.19(3H,t,J≈7.7), 1.21(3H,t,J≈7.7),                            2.61(2H,q,J≈7.7), 2.74(2H,q,J≈7.7),                                                                      343-                                 4.4(4H,m), 7.1-7.5(4H,m)                  341                                                                            339(M.sup.+ +1)             __________________________________________________________________________ 

What is claimed is:
 1. A compound of the formula ##STR420## wherein A is lower alkylene; R₁ is selected from the group consisting of alkyl, phenyl-lower alkyl, and substituted phenyl-lower alkyl;and R is selected from the group consisting of 1-methyltetrazole-5-yl-thio, 1-imidazolyl, morpholino, ##STR421## in which R₅ is hydrogen, lower alkyl or aryl, R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl, Ar is phenyl or phenyl substituted with C₁₋₃ alkyl, halogen, nitro, or lower alkoxy, A and R₁ are as defined above, R₂ and R₃ are each lower alkyl or together form tetramethylene, m is an integer from 4-6, and n is 2 or 3; p1 and pharmaceutically acceptable salts thereof.
 2. The compound of claim 1 wherein R is morpholino.
 3. The compound of claim 1 wherein R is ##STR422## where m is an integer in the range of 4 to
 6. 4. The compound of claim 3 wherein m is 4 or
 5. 5. The compound of claim 1 wherein R is ##STR423## where n is an integer in the range of 2 to
 3. 6. The compound of claim 5 where n is
 2. 7. The compound of claim 1 wherein R is ##STR424## R₆ where R₆ is hydrogen, lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkanoyl, arylcarbonyl, arylsulfonyl or thienyl-lower alkanoyl.
 8. The compound of claim 1 wherein R is ##STR425## 